Sulfonyl containing compounds as cysteine protease inhibitors

ABSTRACT

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of Provisional Patent ApplicationNo. 60/664,139, filed Mar. 22, 2005 the content of which is incorporatedherein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH OR DEVELOPMENT

Not Applicable

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

Not Applicable

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds that are inhibitors ofcysteine proteases, in particular, cathepsins B, K, L, F, and S and aretherefore useful in treating diseases mediated by these proteases. Thepresent invention is also directed to pharmaceutical compositionscomprising these compounds and processes for preparing them.

2. State of the Art

Cysteine proteases represent a class of peptidases characterized by thepresence of a cysteine residue in the catalytic site of the enzyme.Cysteine proteases are associated with the normal degradation andprocessing of proteins. The aberrant activity of cysteine proteases,e.g., as a result of increased expression or enhanced activation,however, may have pathological consequences. In this regard, certaincysteine proteases are associated with a number of disease states,including arthritis, muscular dystrophy, inflammation, tumor invasion,glomerulonephritis, malaria, periodontal disease, metachromaticleukodystrophy and others. For example, increased cathepsin B levels andredistribution of the enzyme are found in tumors; thus, suggesting arole for the enzyme in tumor invasion and metastasis. In addition,aberrant cathepsin B activity is implicated in such disease states asrheumatoid arthritis, osteoarthritis, pneumocystis carinii, acutepancreatitis, inflammatory airway disease and bone and joint disorders.

The prominent expression of cathepsin K in osteoclasts andosteoclast-related multinucleated cells and its high collagenolyticactivity suggest that the enzyme is involved in osteoclast-mediated boneresorption and, hence, in bone abnormalities such as occurs inosteoporosis. In addition, cathepsin K expression in the lung and itselastinolytic activity suggest that the enzyme plays a role in pulmonarydisorders as well.

Cathepsin L is implicated in normal lysosomal proteolysis as well as inseveral disease states, including, but not limited to, metastasis ofmelanomas. Cathepsin S is implicated in Alzheimer's disease and certainautoimmune disorders, including, but not limited to juvenile onsetdiabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease,myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis,neuropathic pain, and Hashimoto's thyroiditis. In addition, cathepsin Sis implicated in: allergic disorders, including, but not limited toasthma; and allogeneic immune reponses, including, but not limited to,rejection of organ transplants or tissue grafts.

In view of the number of diseases wherein it is recognized that anincrease in cysteine protease activity contributes to the pathologyand/or symptomatology of the disease, molecules which inhibit theactivity of this class of enzymes, in particular molecules which inhibitcathepsins B, K, L, F, and/or S, will therefore be useful as therapeuticagents.

SUMMARY OF THE INVENTION

In a first aspect, this invention is directed to a compound of Formula(I):

wherein:

R¹ is hydrogen, alkyl, or haloalkyl;

R² is hydrogen, alkyl, or haloalkyl; or

R¹ and R² taken together with the carbon atom to which R¹ and R² areattached form cycloalkylene optionally substituted with one to fourfluoro, piperidin-4-yl wherein the nitrogen atom of the piperidinyl ringis substituted with alkyl, haloalkyl, or cycloalkyl,tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl,1,1-dioxohexahydrothiopyran-4-yl, or —CH₂—O—CH₂—;

R³ is -alkylene-SO₂-alkyl, -alkylene-SO₂-haloalkyl,-alkylene-SO₂-cycloalkyl, -alkylene-SO₂-cycloalkylalkyl,-alkylene-SO₂-aryl, -alkylene-SO₂-aralkyl,-alkylene-SO₂-heterocycloalkyl, -alkylene-SO₂-heterocycloalkylalkyl,-alkylene-SO₂-heteroaryl, -alkylene-SO₂-heteroaralkyl,-alkylene-SO₂-haloalkylene-aryl or -alkylene-SO₂-haloalkylene-heteroarylwherein the aromatic or alicyclic ring in R³ is optionally substitutedwith one, two, or three R^(a) independently selected from alkyl,alkylsulfonyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkoxy,halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl,cycloalkyl, amino, alkylamino, dialkylamino, aminocarbonyl, or acyl andfurther wherein the aromatic ring in R^(a) is optionally substitutedwith one, two, or three R^(b) independently selected from alkyl, alkoxy,alkylsulfonyl, hydroxy, or halo;

R⁴ is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkylattached via a carbon ring atom wherein the aromatic or alicyclic ringin R⁴ is optionally substituted by one, two, or three R^(f)independently selected from alkyl, halo, hydroxy, alkoxy, alkylcarbonyl,alkylsulfonyl, alkylsulfonylamino, aminocarbonyl, haloalkyl, haloalkoxy,carboxy, or alkoxycarbonyl;

R^(4′) is difluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl,chlorodifluoromethyl, 1,1-dichloro-2,2,2-trifluoroethyl,1,1,2,2-tetrafluoroethyl, trichloromethyl, dichlorofluoromethyl,1,1,2,2,3,3,3-heptafluoropropyl, or 1,1,2,2,3,3-hexafluoropropyl, or apharmaceutically acceptable salt thereof provided that:

(a) when R¹ and R² taken together with the carbon atom to which R¹ andR² are attached form cyclopropylene, R³ is phenylmethanesulfonylmethyl,cyclopropylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl,2-difluoromethoxyphenylmethanesulfonylmethyl, or2-trifluoromethylpyridin-6-methanesulfonylmethyl, R⁴ is phenyl,4-hydroxyphenyl, 3-bromophenyl, 4-fluorophenyl,3-chloro-4-hydroxyphenyl, 3,4-difluorophenyl, or 3,4,5-trifluorophenyl,then R^(4′) is not trifluoromethyl or difluoromethyl;

(b) when R¹ and R² taken together with the carbon atom to which R¹ andR² are attached fotin cyclopropylene, R³ is phenylmethanesulfonylmethyl,difluoromethoxyphenylmethanesulfonylmethyl, orcyclopropylmethanesulfonylmethyl, R⁴ is furan-2-yl, indol-3-yl,thiophen-2-yl, 1-methylpyrrol-2-yl, pyridin-2-yl, thiophen-3-yl or1-oxo-1-methylpyrrol-2-yl, then R^(4′) is not difluoromethyl ortrifluoromethyl;

(c) when R¹ and R² taken together with the carbon atom to which R¹ andR² are attached form 1,1-dioxohexahydrothiopyran-4-ylene, R³ isphenylmethanesulfonylmethyl, 4-fluorophenylmethanesulfonylmethyl, ordifluoromethoxyphenylmethanesulfonylmethyl, then R^(4′) is nottrifluoromethyl; and

(d) when R¹ and R² taken together with the carbon atom to which R¹ andR² are attached form tertrahydropyran-4-ylene ortetrahydrothiopyran-4-ylene, R³ is cyclopropylmethanesulfonylmethyl ordifluoromethoxyphenylmethanesulfonylmethyl, R⁴ is 4-fluorophenyl, thenR⁴: is not trifluoromethyl.

In a second aspect, this invention is directed to a pharmaceuticalcomposition comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in admixture with one or more suitableexcipients.

In a third aspect, this invention is directed to a method for treating adisease in an animal mediated by cysteine proteases, in particularcathepsin S, which method comprises administering to the animal apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula (I) or a pharmaceutically acceptable saltthereof in admixture with one or more suitable excipients.

In a fourth aspect, this invention is directed to processes forpreparing compounds of Formula (I).

In a fifth aspect, this invention is directed to a method of treating apatient undergoing a therapy wherein the therapy causes an immuneresponse, preferably a deleterious immune response, in the patientcomprising administering to the patient a compound of Formula (I) or apharmaceutically acceptable salt thereof. Preferably, the immuneresponse is mediated by MHC class II molecules. The compound of thisinvention can be administered prior to, simultaneously, or after thetherapy. Preferably, the therapy involves treatment with a biologic.Preferably, the therapy involves treatment with a small molecule.

Preferably, the biologic is a protein, preferably an antibody, morepreferably monoclonal antibody. More preferrably, the biologic isRemicade®, Refacto®, ReferonA®, Factor VIII, Factor VII, Betaseron®,Epogen®, Enbrel®, Interferon beta, Botox®, Fabrazyme®, Elspar®,Cerezyme®, Myobloc®, Aldurazyme®, Verluma®, Interferon alpha, Humira®,Aranesp®, Zevalin® or OKT3.

Preferably, the treatment involves use of heparin, low molecular weightheparin, procainamide or hydralazine.

In a sixth aspect, this invention is directed to a method of treatingimmune response in an animal that is caused by administration of abiologic to the animal which method comprises administering to theanimal in need of such treatment a therapeutically effective amount of acompound of Fomiula (I) or a pharmaceutically acceptable salt thereof.

In a seventh aspect, this invention is directed to a method ofconducting a clinical trial for a biologic comprising administering toan individual participating in the clinical trial a compound of Formula(I) or a pharmaceutically acceptable salt thereof with the biologic.

In an eight aspect, this invention is directed to a method ofprophylactically treating a patient undergoing treatment with a biologicwith a compound of Formula (I) or a pharmaceutically acceptable saltthereof to treat the immune response caused by the biologic in thepatient.

In a ninth aspect, this invention is directed to a method of determiningthe loss in the efficacy of a biologic in an animal due to the immuneresponse caused by the biologic comprising administering the biologic tothe animal in the presence and absence of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In a tenth aspect, this invention is directed to a method of improvingefficacy of a biologic in an animal comprising administering thebiologic to the animal with a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In an eleventh aspect, this invention is directed to the use of acompound of Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament. Preferably, the medicament is foruse in the treatment of a disease mediated by Cathepsin S.

In a twelfth aspect, this invention is directed to the use of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for combination therapy with a biologic,wherein the compound of this invention treats the immune response causedby the biologic. Preferably, the compound(s) of the invention isadministered prior to the administration of the biological agent.Preferably, the compound(s) of the invention is administeredconcomitantly with the biological agent. Preferably, the compound(s) ofthe invention is administered after the administration of the biologicalagent.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meanings.

“Alicyclic” means a moiety characterized by arrangement of the carbonatoms in closed non-aromatic ring structures e.g., cycloalkyl andheterocycloalkyl rings as defined herein.

“Alkyl” represented by itself means a straight or branched, saturatedaliphatic radical containing one to eight carbon atoms, unless otherwiseindicated e.g., alkyl includes methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, and the like.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated aliphatic, divalent radical having the number of one to sixcarbon atoms, e.g., methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—) 2-methyltetramethylene(—CH₂CH(CH₃)CH₂CH₂—), pentamethylene (—CH₂CH₂CH₂CH₂CH₂—), and the like.

“Alkoxy” refers to a —OR radical where R is an alkyl group as definedabove e.g., methoxy, ethoxy, and the like.

“Alkylsulfonyl” refers to a —SO₂R radical where R is an alkyl group asdefined above e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Alkylsulfonylamino” refers to a —NHSO₂R radical where R is an alkylgroup as defined above e.g., methylsulfonylamino, ethylsulfonylamino,and the like.

“Alkoxycarbonyl” refers to a —C(O)OR radical where R is an alkyl groupas defined above e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Amino” means —NH₂ radical.

“Aminocarbonyl” refers to a —CONRR′ radical where R and R′ areindependently hydrogen or alkyl, e.g., —CONH₂, methylaminocarbonyl,dimethylaminocarbonyl, and the like.

“Alkylamino” or “dialkylamino” refers to a —NHR and —NRR′ radicalrespectively, where R and R′ are independently alkyl group as definedabove e.g., methylamino, dimethylamino, and the like.

“Acyl” means a —COR radical where R is alkyl, haloalkyl, aryl,heteroaryl, or heterocycloalkyl as defined herein e.g., acetyl,trifluoroacetyl, and the like. When R is alkyl it is referred to hereinas alkylcarbonyl.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” refers to a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2.

“Aryl” refers to a monocyclic or fused bicyclic ring assembly containing6 to 10 ring carbon atoms wherein each ring is aromatic e.g., phenyl ornaphthyl.

“Aralkyl” refers to a -(alkylene)-aryl radical where alkylene and arylare as defined above, e.g., benzyl, 2-phenylethyl, and the like.

“Biologic” means a therapeutic agent originally derived from livingorganisms for the treatment or management of a disease. Examplesinclude, but are not limited to, proteins (recombinant and plasmaderived), monoclonal or polyclonal, humanized or murine antibodies,toxins, hormones, and the like. Biologics are currently available forthe treatment of a variety of diseases such as cancer, rheumatoidarthritis, and hemophilia.

“Carboxy” refers to —C(O)OH radical.

“Cycloalkyl” refers to a monovalent saturated monocyclic ring containingthree to eight ring carbon atoms e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

“Cycloalkylalkyl” refers to a -(alkylene)-R radical where R iscycloalkyl as defined above e.g., cyclopropylmethyl, cyclobutylethyl,cyclobutylmethyl, and the like

“Cycloalkylene” refers to a divalent saturated monocyclic ringcontaining three to eight ring carbon atoms. For example, the instancewherein “R¹ and R² together with the carbon atom to which both R¹ and R²are attached form cycloalkylene” includes, but is not limited to, thefollowing:

and the like.

“Derived” means a similar agent can be traced to.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Deleterious immune response” means an immune response that preventseffective treatment of a patient or causes disease in a patient. As anexample, dosing a patient with a murine antibody either as a therapy ora diagnostic agent causes the production of human antimouse antibodiesthat prevent or interfere with subsequent treatments. The incidence ofantibody formation versus pure murine monoclonals can exceed 70%. (seeKhazaeli, M. B. et al. J. Immunother. 1994, 15, pp 42-52; Dillman R. O.et al. Cancer Biother. 1994, 9, pp 17-28; and Reinsberg, J. Hybridoma.1995, 14, pp 205-208). Additional examples of known agents that sufferfrom deleterious immune responses are blood-clotting factors such asfactor VIII. When administered to hemophilia A patients, factor VIIIrestores the ability of the blood to clot. Although factor VIII is ahuman protein, it still elicits an immune response in hemophiliacs asendogenous factor VIII is not present in their blood and thus it appearsas a foreign antigen to the immune system. Approximately 29-33% of newpatients will produce antibodies that bind and neutralize thetherapeutically administered factor VIII (see Lusher J. M. Semin ThrombHemost. 2002, 28(3), pp 273-276). These neutralizing antibodies requirethe administration of larger amounts of factor VIII in order to maintainnormal blood clotting parameters; an expensive regimen of treatment inorder to induce immune tolerance (see Briet E et al. Adv. Exp. Med. Bio.2001, 489, pp 89-97). Another immunogenic example is adenoviral vectors.Retroviral therapy remains experimental and is of limited utility. Onereason is that the application of a therapeutic virus generates animmune response capable of blocking any subsequent administration of thesame or similar virus (see Yiping Yang et al. J. of Virology. 1995, 69,pp 2004-2015). This ensures that retroviral therapies must be based onthe transient expression of a protein or the direct incorporation ofviral sequence into the host genome. Directed research has identifiedmultiple viral neutralizing epitopes recognized by host antibodies (seeHanne, Gahery-Segard et al. J. of Virology 1998. 72, pp 2388-2397)suggesting that viral modifications will not be sufficient to overcomethis obstacle. This invention will enable a process whereby anadenoviral therapy will have utility for repeated application. Anotherexample of an immunogenic agent that elicits neutralizing antibodies isthe well-known cosmetic agent Botox. Botulin toxin protein, is purifiedfrom the fermentation of Clostridium botulinum. As a therapeutic agent,it is used for muscle disorders such as cervical dystonia in addition tocosmetic application. After repeated exposure patients generateneutralizing antibodies to the toxin that results in reduced efficacy(see Birklein F. et al. Ann Neurol. 2002, 52, pp 68-73 and Rollnik, J.D. et al. Neurol. Clin. Neurophysiol. 2001, 2001(3), pp 2-4). A“deleterious immune response” also encompasses diseases caused bytherapeutic agents. A specific example of this is the immune response totherapy with recombinant human erythropoietin (EPO). Erythropoietin isused to stimulate the growth or red cells and restore red blood cellcounts in patients who have undergone chemotherapy or dialysis. A smallpercentage of patients develop antibodies to EPO and subsequently areunresponsive to both therapeutically administered EPO and their ownendogenous EPO (see Casadevall, N. et al., NEJM. 2002, 346, pp 469-475).They contract a disorder, pure red cell aplasia, in which red blood cellproduction is severely diminished (see Gershon S. K. et. al. NEJM. 2002,346, pp 1584-1586). This complication of EPO therapy is lethal ifuntreated. Another specific example is the murine antibody, OKT3(a.k.a., Orthoclone) a monoclonal antibody directed towards CD-3 domainof activated T-cells. In clinical trials 20-40% of patients administeredOKT3 produce antibodies versus the therapy. These antibodies, besidesneutralizing the therapy, also stimulate a strong host immune reaction.The immune reaction is severe enough that patients with high titers ofhuman anti-mouse antibodies are specifically restricted from taking thedrug (see Orthoclone package label). A final example is a human antibodytherapeutic. Humira® is a monoclonal antibody directed against TNF andis used to treat rheumatoid arthritis patients. When taken alone ˜12% ofpatients develop neutralizing antibodies. In addition, a smallpercentage of patients given the drug also contract a systemic lupuserthematosus-like condition that is an IgG-mediated immune responseinduced by the therapeutic agent (see Humira package label).

Another example of “deleterious immune response” is a host reaction tosmall molecule drugs. It is known to those skilled in the art thatcertain chemical structures will conjugate with host proteins tostimulate immune recognition (see Ju. C. et al. 2002. Current DrugMetabolism 3, pp 367-377 and Kimber I. et al. 2002, ToxicologicPathology 30, pp 54-58.) A substantial portion of these host reactionsare IgG mediated. Specific “deleterious immune responses” that are IgGmediated include: hemolytic anemia, Steven-Johnson syndrome and druginduced Lupus.

“Halo” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to alkyl as defined above substituted by one or more,preferably one to seven, “halo” atoms, as such terms are defined in thisApplication. Haloalkyl includes monohaloalkyl, dihaloalkyl,trihaloalkyl, perhaloalkyl and the like e.g. chloromethyl,dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).

“Haloalkylene” means alkylene radical as defined above wherein one tofour, preferably one or two hydrogen atoms in the alkylene chainhas(have) been replaced by fluorine atom(s).

“Haloalkoxy” refers to a —OR radical where R is haloalkyl group asdefined above e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy,difluoromethoxy, and the like.

“Heteroaryl” as a group or part of a group denotes an aromaticmonocyclic, bicyclic, or multicyclic moiety of 5 to 10 ring atoms inwhich one or more, preferably one, two, or three, of the ring atom(s)is(are) selected from nitrogen, oxygen or sulfur, the remaining ringatoms being carbon. Representative heteroaryl rings include, but are notlimited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolyl, andthe like.

“Heteroaralkyl” refers to a -(alkylene)-heteroaryl radical wherealkylene and heteroaryl are as defined above, e.g., pyridinylmethyl,pyridinylethyl, pyrimidinylmethyl, and the like.

“Heterocycloalkyl” refers to a saturated or partially unsaturated,monocyclic or bicyclic moiety of 4, 5 or 6 carbon ring atoms wherein oneor more, preferably one, two, or three of the carbon ring atoms arereplaced by a heteroatom selected from —N═, —N—, —O—, —S—, —SO—, or—S(O)₂— and further wherein one or two ring atoms are optionallyreplaced by a keto (—CO—) group. The heterocycloalkyl ring is optionallyfused to cycloalkyl, aryl or heteroaryl ring as defined herein.Representative examples include, but are not limited to,4-oxo-5-aza-benzospiro[2.4]hept-5-yl, imidazolidinyl, morpholinyl,thiomorpholinyl, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl,1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetrathiopyranyl, indolinyl,piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, and the like.

“Heterocycloalkylalkyl” refers to a -(alkylene)-R radical where R isheterocycloalkyl as defined above e.g., pyrrolidinylmethyl,tetrahydrofuranylethyl, pyridinylmethyl, and the like.

“Hydroxy” means —OH radical. Unless indicated otherwise, the compoundsof the invention containing hydroxy radicals include protectedderivatives thereof. Suitable protecting groups for hydroxy moietiesinclude benzyl and the like.

“Hydroxyalkyl” refers to alkyl as defined above substituted by one ormore, preferably one to three hydroxyl groups e.g., hydroxymethyl,hydroxyethyl, and the like.

“Isomers” mean compounds of Formula (I) having identical molecularformulae but differ in the nature or sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers”. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”. A compound with one chiral center that has two enantiomericforms of opposite chirality is termed a “racemic mixture”. A compoundthat has more than one chiral center has 2^(n-1) enantiomeric pairs,where n is the number of chiral centers. Compounds with more than onechiral center may exist as either an individual diastereomer or as amixture of diastereomers, termed a “diastereomeric mixture”. When onechiral center is present a stereoisomer may be characterized by theabsolute configuration of that chiral center. Absolute configurationrefers to the arrangement in space of the substituents attached to thechiral center. Enantiomers are characterized by the absoluteconfiguration of their chiral centers and described by the R- andS-sequencing rules of Cahn, Ingold and Prelog. Conventions forstereochemical nomenclature, methods for the determination ofstereochemistry and the separation of stereoisomers are well known inthe art (e.g., see “Advanced Organic Chemistry”, 4th edition, March,Jerry, John Wiley & Sons, New York, 1992). It is understood that thenames and illustration used in this application to describe compounds ofFormula (I) are meant to be encompassed all possible stereoisomers.

“Optional” or “optionally” or “may be” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, the phrase “wherein thearomatic ring in R^(a) is optionally substituted with one or twosubstituents independently selected from alkyl” means that the aromaticring may or may not be substituted with alkyl in order to fall withinthe scope of the invention.

The present invention also includes N-oxide derivatives of a compound ofFormula (I). N-oxide derivative mean a compound of Formula (I) in whicha nitrogen atom is in an oxidized state (i.e., N→O) e.g., pyridineN-oxide, and which possess the desired pharmacological activity.

“Pathology” of a disease means the essential nature, causes anddevelopment of the disease as well as the structural and functionalchanges that result from the disease processes.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of Formula(I) which are pharmaceutically acceptable, as defined above, and whichpossess the desired pharmacological activity. Such salts include acidaddition salts formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or with organic acids such as acetic acid, propionic acid,hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxy-ethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

The present invention also includes prodrugs of a compound of Formula(I). Prodrug means a compound that is convertible in vivo by metabolicmeans (e.g. by hydrolysis) to a compound of Formula (I). For example anester of a compound of Formula (I) containing a hydroxy group may beconvertible by hydrolysis in vivo to the parent molecule. Alternativelyan ester of a compound of Formula (I) containing a carboxy group may beconvertible by hydrolysis in vivo to the parent molecule. Suitableesters of compounds of Formula (I) containing a hydroxy group, are forexample acetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methylsulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates. Suitable esters of compounds of Formula (I) containing acarboxy group, are for example those described by Leinweber, F. J. DrugMetab. Res., 1987, 18, page 379. An especially useful class of esters ofcompounds of Formula (I) containing a hydroxy group, may be formed fromacid moieties selected from those described by Bundgaard et al., J. Med.Chem., 1989, 32, pp 2503-2507, and include substituted(aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates inwhich the two alkyl groups may be joined together and/or interrupted byan oxygen atom or by an optionally substituted nitrogen atom, e.g. analkylated nitrogen atom, more especially (morpholino-methyl)benzoates,e.g. 3- or 4-(morpholinomethyl)-benzoates, and(4-alkylpiperazin-1-yl)benzoates, e.g. 3- or4-(4-alkylpiperazin-1-yl)benzoates.

“Protected derivatives” means derivatives of compounds of Formula (I) inwhich a reactive site or sites are blocked with protecting groups.Protected derivatives of compounds of Formula (I) are useful in thepreparation of compounds of Formula (I) or in themselves may be activecathepsin S inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protective Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,reversing the pathology and/or symptomatology).

“Treatment” or “treating” with respect to combination therapy i.e., usewith a biologic means any administration of a compound of the presentinvention and includes:

(1) preventing the immune response from occurring in an animal which maybe predisposed to the immune response but does not yet experience ordisplay the pathology or symptomatology of the immune response,(2) inhibiting the immune response in an animal that is experiencing ordisplaying the pathology or symptomatology of the immune response (i.e.,arresting further development of the pathology and/or symptomatology),or(3) ameliorating the immune response in an animal that is experiencingor displaying the pathology or symptomatology of the immune response(i.e., reducing in degree or severity, or extent or duration, the overtmanifestations of the immune response or reversing the pathology and/orsymptomatology e.g., reduced binding and presentation of antigenicpeptides by MHC class II molecules, reduced activation of T-cells andB-cells, reduced humoral and cell-mediated responses and, as appropriateto the particular immune response, reduced inflammation, congestion,pain, necrosis, reduced loss in the efficacy of a biologic agent, andthe like).

The expression “ . . . wherein the aromatic or alicyclic ring in R³ isoptionally substituted with one, two, or three R^(a) independentlyselected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, amino,alkylamino, dialkylamino, or acyl . . . ” includes instances where thearomatic or alicyclic ring is directly linked to R³ or where thearomatic or alicyclic ring is part of a group that is directly linked toR³ e.g., the alicyclic and aromatic ring in-alkylene-SO₂-cycloalkylalkyl, -alkylene-SO₂-aralkyl,-alkylene-SO₂-heterocycloalkylalkyl, -alkylene-SO₂-heteroaralkyl, or-alkylene-SO₂-haloalkylene-heteroaryl groups that are attached to R³ mayor may not be substituted with R^(a) group(s).

Preferred Embodiments

I. Certain compounds of Formula (I) within the broadest scope set forthin the Summary of the Invention are preferred. For example:

A. One preferred group of compounds is that wherein R¹ and R² arehydrogen.

B. Another preferred group of compounds is that wherein R¹ and R²together with the carbon atom to which they are attached formcycloalkylene, preferably R¹ and R² together with the carbon atom towhich they are attached form cyclopropylene.

C. Another preferred group of compounds is that wherein R¹ and R²together with the carbon atom to which they are attached formtetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or1,1-dioxohexahydrothiopyran-4-yl.

(a) Within the above preferred groups A, B, and C and the more preferredgroups contained therein, a more preferred group of compounds is thatwherein:

R³ is -alkylene-SO₂— heteroaralkyl, preferably the heteroaryl ring inthe heteroaralkyl moiety is pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, quinolinyl, or isoquinolinyl and wherein the heteroarylring is optionally substituted with one, two, or three R^(a)independently selected from alkyl, haloalkyl, alkoxy, hydroxy,haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl,heteroaryl, amino, alkylamino, dialkylamino, or acyl and further whereinthe aromatic ring in R^(a) is optionally substituted with one, two, orthree R^(b) independently selected from alkyl, alkoxy, hydroxyl, orhalo. Preferably, R³ is 4-CF₃-pyridin-3-ylmethane-sulfonylmethyl,pyridin-3-ylmethanesulfonylmethyl, pyridazin-3-ylmethanesulfonylmethyl,2-CF₃-furan-5-ylmethanesulfonylmethyl,pyrimidin-5-ylmethanesulfonylmethyl,2-CH₃-thiazol-4-ylmethanesulfonylmethyl, orpyridin-4-ylmethane-sulfonylmethyl.

(b) Within the above preferred groups A, B, and C and the more preferredgroups contained therein, another even more preferred group of compoundsis that wherein:

R³ is -alkylene-SO₂—CF₂-heteroaryl, preferably preferably the heteroarylring in the heteroaralkyl moiety is pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, quinolinyl, or isoquinolinyl and wherein the heteroarylring is optionally substituted with one, two, or three R^(a)independently selected from alkyl, haloalkyl, alkoxy, hydroxy,haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl,heteroaryl, amino, alkylamino, dialkylamino, or acyl and further whereinthe aromatic ring in R^(a) is optionally substituted with one, two, orthree R^(b) independently selected from alkyl, alkoxy, hydroxyl, orhalo. Preferably, R³ is 4-CF₃-pyridin-3-yl-CF₂SO₂-methyl,pyridin-3-yl-CF₂SO₂-methyl, pyridazin-3-yl-CF₂SO₂-methyl,pyrimidin-5-yl-CF₂SO₂-methyl, or pyridin-4-yl-CF₂SO₂-methyl.

Within the above preferred groups A, A(a-b), B, B(a-b), C, and C(a-b)and the more preferred groups contained therein, a particularlypreferred group of compounds is that wherein:

R⁴ is phenyl optionally substituted with one or two fluoro. Preferably,R⁴ is 4-fluorophenyl, 2,4-difluorophenyl, or 3,4-difluorophenyl;

and the stereochemistry at the carbon to which R³ is attached is (R) andto which R⁴ is attached is (S).

(D) Another preferred group of compounds is that wherein:

R¹ and R² form cyclopropylene;

R³ is 4-CF₃-pyridin-3-ylmethanesulfonylmethyl,pyridin-3-ylmethanesulfonylmethyl, pyridazin-3-ylmethanesulfonylmethyl,2-CF₃-furan-5-ylmethanesulfonylmethyl,pyrimidin-5-ylmethanesulfonylmethyl,2-CH₃-thiazol-4-ylmethanesulfonylmethyl,pyridin-4-ylmethane-sulfonylmethyl, pyrimidin-4-ylmethanesulfonylmethyl,2-(1-oxopyrrol-1-yl)ethanesulfonyl-methyl,cyclopropylmethanesulfonylmethyl,3,3,3-trifluoropropane-1-sulfonylmethyl,2-CF₃-pyridin-5-ylmethanesulfonylmethyl,4-[1.2.4]-triazol-1-ylphenylmethanesulfonylmethyl,2-(2-oxo-2,3-dihydrobenzimidazol-1-yl)-ethanesulfonylmethyl,5-oxopyrrolidin-2-ylmethane-sulfonylmethyl,2-F-pyridin-3-ylmethanesulfonylmethyl,3-CH₃-oxetan-3-ylmethanesulfonyl-methyl, 2-phenylethanesulfonylmethyl,fluoro-pyridin-2-ylmethanesulfonylmethyl,fluoro-pyrazin-2-ylmethanesulfonylmethyl,difluoro-pyridin-2-ylmethanesulfonylmethyl,difluoro-pyridin-3-ylmethanesulfonylmethyl,quinolin-2-ylmethanesulfonylmethyl,benzo[1.2.5]thiadiazol-4-ylmethanesulfonylmethyl,benzothiazol-2-ylmethanesulfonylmethyl,5-methylisoxazol-3-ylmethanesulfonylmethyl,2-methylpropyl-sulfonylmethyl, 2,6-difluorophenylmethanesulfonylmethyl,2,4-difluorophenylmethane-sulfonylmethyl,quinolin-3-ylmethanesulfonylmethyl,4,4,4-trifluorobutyl-1-sulfonylmethyl,2-CF₃-phenylmethanesulfonylmethyl, 2-CF₃O-phenylmethanesulfonylmethyl,2-pyridin-2-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl,quinolin-8-ylmethane-sulfonylmethyl,5-methyl-3-phenylisoxazol-4-ylmethanesulfonylmethyl,4-methyl-2-phenyl-[1.2.3]triazol-5-ylmethanesulfonylmethyl,2-cyanophenylmethanesulfonylmethyl,3-methoxycarbonylphenylmethanesulfonylmethyl,pyridin-2-ylmethanesulfonylmethyl,1-oxopyridin-2-ylmethanesulfonylmethyl,1-oxopyridin-3-ylmethanesulfonylmethyl,quinoxalin-2-ylmethanesulfonylmethyl,tetrahydropyran-2RS-ylmethanesulfonylmethyl,2,6-dichloro-phenylmethanesulfonylmethyl,3-methoxycarbonyl-furan-2-yl-methanesulfonylmethyl,5-methylisoxazol-3-ylmethanesulfonylmethyl,2,2-dimethylpropylsulfonylmethyl, ethanesulfonylmethyl,methanesulfonylmethyl, propane-1-sulfonylmethyl,1H-indol-2-ylmethanesulfonylmethyl,2-(1H-indol-3-yl)ethanesulfonylmethyl,2,2,2-trifluoroethanesulfonylmethyl,benzisoxazol-3-ylmethanesulfonylmethyl,2-tert-butyl-[1.3.4]thiadiazol-5-ylmethanesulfonylmethyl,2,4,6-trifluorophenylmethanesulfonylmethyl,2-pyridin-2-ylethanesulfonylmethyl,1-ethyl-2,5-dioxopyrrolidin-3-ylmethanesulfonylmethyl orbenzisoxazol-3-ylmethanesulfonylmethyl;

R⁴ is 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, or 3,5-difluorophenyl, more preferably2,4-difluorophenyl;

R^(4′) is difluoromethyl, trifluoromethyl, or1,1,2,2,2-pentafluoroethyl, more preferably trifluoromethyl.

(D) Another preferred group of compounds is that wherein:

R¹ and R² form cyclopropylene;

R³ is 4-CF₃-pyridin-3-ylmethanesulfonylmethyl,pyridin-3-ylmethanesulfonylmethyl, pyridazin-3-ylmethanesulfonylmethyl,2-CF₃-furan-5-ylmethanesulfonylmethyl,pyrimidin-5-ylmethanesulfonylmethyl,2-CH₃-thiazol-4-ylmethanesulfonylmethyl,pyridin-4-ylmethane-sulfonylmethyl, pyrimidin-4-ylmethanesulfonylmethyl,2-(1-oxopyrrol-1-yl)ethanesulfonyl-methyl,cyclopropylmethanesulfonylmethyl,3,3,3-trifluoropropane-1-sulfonylmethyl,2-CF₃-pyridin-5-ylmethanesulfonylmethyl,4-[1.2.4]-triazol-1-ylphenylmethanesulfonylmethyl,2-(2-oxo-2,3-dihydrobenzimidazol-1-yl)-ethanesulfonylmethyl,5-oxopyrrolidin-2-ylmethane-sulfonylmethyl,2-F-pyridin-3-ylmethanesulfonylmethyl,3-CH₃-oxetan-3-ylmethanesulfonyl-methyl, 2-phenylethanesulfonylmethyl,fluoro-pyridin-2-ylmethanesulfonylmethyl,fluoro-pyrazin-2-ylmethanesulfonylmethyl,difluoro-pyridin-2-ylmethanesulfonylmethyl,difluoro-pyridin-3-ylmethanesulfonylmethyl,quinolin-2-ylmethanesulfonylmethyl,benzo[1.2.5]thiadiazol-4-ylmethanesulfonylmethyl,benzothiazol-2-ylmethanesulfonylmethyl,5-methylisoxazol-3-ylmethanesulfonylmethyl,2-methylpropyl-sulfonylmethyl, 2,6-difluorophenylmethanesulfonylmethyl,2,4-difluorophenylmethane-sulfonylmethyl,quinolin-3-ylmethanesulfonylmethyl,4,4,4-trifluorobutyl-1-sulfonylmethyl,2-CF₃-phenylmethanesulfonylmethyl, 2-CF₃O-phenylmethanesulfonylmethyl,2-pyridin-2-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl,quinolin-8-ylmethane-sulfonylmethyl,5-methyl-3-phenylisoxazol-4-ylmethanesulfonylmethyl,4-methyl-2-phenyl-[1.2.3]triazol-5-ylmethanesulfonylmethyl,2-cyanophenylmethanesulfonylmethyl,3-methoxycarbonylphenylmethanesulfonylmethyl,pyridin-2-ylmethanesulfonylmethyl,1-oxopyridin-2-ylmethanesulfonylmethyl,1-oxopyridin-3-ylmethanesulfonylmethyl,quinoxalin-2-ylmethanesulfonylmethyl,tetrahydropyran-2RS-ylmethanesulfonylmethyl,2,6-dichloro-phenylmethanesulfonylmethyl,3-methoxycarbonyl-furan-2-yl-methanesulfonylmethyl,5-methylisoxazol-3-ylmethanesulfonylmethyl,2,2-dimethylpropylsulfonylmethyl, ethanesulfonylmethyl,methanesulfonylmethyl, propane-1-sulfonylmethyl,1H-indol-2-ylmethanesulfonylmethyl,2-(1H-indol-3-yl)ethanesulfonylmethyl,2,2,2-trifluoroethanesulfonylmethyl,benzisoxazol-3-ylmethanesulfonylmethyl,2-tert-butyl-[1.3.4]thiadiazol-5-ylmethanesulfonylmethyl,2,4,6-trifluorophenylmethanesulfonylmethyl,2-pyridin-2-ylethanesulfonylmethyl,1-ethyl-2,5-dioxopyrrolidin-3-ylmethanesulfonylmethyl orbenzisoxazol-3-ylmethanesulfonylmethyl;

R⁴ is hydrogen;

R^(4′) is difluoromethyl, trifluoromethyl, or1,1,2,2,2-pentafluoroethyl, more preferably trifluoromethyl.

(F) Yet another preferred group of compounds is that wherein R³ is-alkylene-SO₂-haloalkylene-heteroaryl, more preferably-alkylene-SO₂—CF₂-heteroaryl.

Within this preferred group a more preferred group is that wherein R¹and R² are cyclopropylene.

(G) Yet another preferred group of compounds is that wherein:

R³ is 3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl;2-CF₃-methylphenylmethane-sulfonylmethyl,3-CF₃pyridin-2-ylmethanesulfonylmethyl,2-F-furan-5-ylmethanesulfonyl-methyl,2-methylthiazol-4-ylmethanesulfonylmethyl,tetrahydropyran-4-ylmethane-sulfonylmethyl,1,1-dioxo-1λ⁶-hexahydrothiopyran-4-ylmethanesulfonylmethyl,1-ethylpiperidin-4-ylmethanesulfonylmethyl,2-oxo-tetrahydropyrimidin-4-ylmethane-sulfonylmethyl,1-ethyl-2-oxopiperidin-4-ylmethanesulfonylmethyl,1-acetylpiperidin-4-ylmethanesulfonylmethyl,1-ethoxycarbonylpiperidin-4-ylmethanesulfonylmethyl,1-methylsulfonylpiperidin-4-ylmethanesulfonylmethyl,1-cyclopropylpiperidin-4-ylmethane-sulfonylmethyl,1-acetylazetidin-3-ylmethanesulfonylmethyl,1-ethoxycarbonylazetidin-3-ylmethanesulfonylmethyl,1-methylsulfonylazetidin-3-ylmethanesulfonylmethyl,1-ethylazetidin-3-ylmethanesulfonylmethyl,1-cyclopropylazetidin-3-ylmethanesulfonylmethylfuran-2-ylmethanesulfonylmethyl,difluoro-(4-fluorophenyl)methanesulfonylmethyl,difluoro-(pyrazin-2-yl)methanesulfonylmethyl,difluoro-(2-difluoromethoxyphenyl)-methanesulfonylmethyl,1-acetylpiperidin-4-ylsulfonylmethyl,1-ethoxycarbonylpiperidin-4-ylsulfonylmethyl,1-cyclopropyllpiperidin-4-ylsulfonylmethyl,2-(pyridin-2-yl)ethanesulfonyl-methyl,2-(pyridin-3-yl)ethanesulfonylmethyl,2-(pyridin-4-yl)ethanesulfonylmethyl,3-(pyridin-2-yl)propanesulfonylmethyl,2,6-difluorophenylmethanesulfonyl,[1.3.5]triazin-2-ylmethanesulfonylmethyl,[1.3.4]thiadiazol-2-ylmethanesulfonylmethyl,oxazol-5-ylmethane-sulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl,4-fluorophenylmethanesulfonylmethyl,4-aminocarbonylphenylmethanesulfonylmethyl,4-piperazin-4-ylphenylmethanesulfonylmethyl,5-fluoroindol-3-ylmethanesulfonylmethyl,4,6-difluoroindol-3-ylmethanesulfonylmethyl,1-methylindol-3-ylmethanesulfonylmethyl,4-fluoroindol-3-ylmethanesulfonylmethyl,2-(5-fluoroindol-3-yl)ethanesulfonylmethyl,2-(4,6-difluoroindol-3-yl)ethanesulfonylmethyl,2-(1-methylindol-3-yl)ethanesulfonylmethyl,2-(4-fluoroindol-3-yl)ethanesulfonylmethyl,2-quinolin-3-ylethanesulfonylmethyl,2-quinolin-2-ylethanesulfonylmethyl,isoquinolin-3-ylmethane-sulfonylmethyl,2-(isoquinolin-3-yl)ethanesulfonylmethyl,2,4-difluoropyridin-3-ylmethane-sulfonylmethyl,3,4-difluoropyridin-4-ylmethanesulfonylmethyl,2-(2,4-difluoropyridin-3-yl)ethanesulfonylmethyl,2-(3,4-difluoropyridin-4-yl)ethanesulfonylmethyl,fluoro-(2,4-difluoropyridin-3-yl)methanesulfonylmethyl,fluoro-(3,4-difluoropyridin-4-yl)methane-sulfonylmethyl,2,4-diCF₃pyridin-3-ylmethanesulfonylmethyl,3,4-diCF₃pyridin-4-ylmethane-sulfonylmethyl,2-(2,4-diCF₃pyridin-3-yl)ethanesulfonylmethyl,diCF₃pyridin-4-ylmethanesulfonylmethyl,fluoro-(2,4-diCF₃pyridin-3-yl)methanesulfonylmethyl,fluoro-(3,4-diCF₃pyridin-4-ylmethanesulfonylmethyl,4-F-pyridin-3-ylmethanesulfonylmethyl,3-F-pyridin-5-ylmethanesulfonylmethyl,2-F-pyridin-5-ylmethanesulfonylmethyl,2-F-pyridin-3-ylmethanesulfonylmethyl,5-F-pyridin-2-ylmethanesulfonylmethyl,4-F-pyridin-2-ylmethane-sulfonylmethyl,4-F-1-oxopyridin-3-ylmethanesulfonylmethyl,3-F-1-oxopyridin-5-ylmethane-sulfonylmethyl,2-F-1-oxopyridin-5-ylmethanesulfonylmethyl,2-F-1-oxopyridin-3-ylmethane-sulfonylmethyl,5-F-1-oxopyridin-2-ylmethanesulfonylmethyl,4-F-1-oxopyridin-2-ylmethane-sulfonylmethyl,4-CF₃-pyridin-2-ylmethanesulfonylmethyl,3-CF₃-pyridin-5-ylmethane-sulfonylmethyl,3-F-pyridin-2-ylmethanesulfonylmethyl,2-CF₃-pyridin-3-ylmethane-sulfonylmethyl,4-CF₃-1-oxopyridin-2-ylmethanesulfonylmethyl,3-CF₃-1-oxopyridin-5-ylmethanesulfonylmethyl,3-F-1-oxopyridin-2-ylmethanesulfonylmethyl,2-CF₃-1-oxopyridin-3-ylmethanesulfonylmethyl,5-CF₃-1-oxopyridin-2-ylmethanesulfonylmethyl,2-CH₃-pyridin-6-ylmethanesulfonylmethyl,3-CH₃-pyridin-2-ylmethanesulfonylmethyl,4-CH₃-pyridin-3-ylmethanesulfonylmethyl,3-CH₃-pyridin-4-ylmethanesulfonylmethyl,2-(2-CH₃-pyridin-6-yl)ethanesulfonylmethyl,2-(3-CF₃-pyridin-2-ylmethanesulfonylmethyl,2-(4-CF₃-pyridin-3-yl)ethanesulfonylmethyl,2-(3-CF₃-pyridin-4-yl)ethanesulfonylmethyl,2-C₂H₅-pyridin-6-ylmethanesulfonylmethyl,3-C₂H₅-pyridin-2-ylmethanesulfonylmethyl,4-C₂H₅-pyridin-3-ylmethanesulfonylmethyl,3-C₂H₅-pyridin-4-ylmethanesulfonylmethyl,2-(2-C₂H₅-pyridin-6-ylmethanesulfonylmethyl,2-(3-C₂H₅-pyridin-2-yl)ethanesulfonylmethyl,2-(4-C₂H₅-pyridin-3-yl)ethanesulfonylmethyl,2-(3-C₂H₅-pyridin-4-yl)ethanesulfonylmethyl,2-(2-CH₃-pyridin-3-ylmethanesulfonylmethyl,2-CF₃-pyridin-3-ylmethanesulfonylmethyl,2-(3-CF₃-pyridin-4-yl)ethanesulfonylmethyl,3-CF₃-pyridin-4-ylmethanesulfonylmethyl,cinnolin-3-ylmethane-sulfonylmethyl,2-(cinnolin-3-yl)ethanesulfonylmethyl,phthalazin-1-ylmethanesulfonylmethyl,2-(phthalazin-1-yl)ethanesulfonylmethyl,2-(quinoxalin-2-yl)ethanesulfonylmethyl,quinazolin-2-ylmethanesulfonylmethyl,2-(quinazolin-2-yl)ethanesulfonylmethyl,[1,8]naphthyridin-2-ylmethanesulfonylmethyl,2-([1,8]naphthyridin-2-ylmethanesulfonylmethyl,[1,8]naphthyridin-3-ylmethanesulfonylmethyl,2-([1,8]naphthyridin-3-yl)ethanesulfonylmethyl,3-Cl-pyridin-2-ylmethanesulfonylmethyl,4-Cl-pyridin-3-ylmethanesulfonylmethyl,3-Cl-pyridin-4-ylmethane-sulfonylmethyl,3-F-pyridin-2-ylmethanesulfonylmethyl,4-F-pyridin-3-ylmethanesulfonyl-methyl,3-F-pyridin-4-ylmethanesulfonylmethyl,isoquinolin-4-ylmethanesulfonylmethyl,6-phenylpyridin-2-ylmethanesulfonylmethyl,3-phenylpyridin-2-ylmethanesulfonylmethyl,4-phenylpyridin-3-ylmethanesulfonylmethyl,3-phenylpyridin-4-ylmethanesulfonylmethyl,2-(6-phenylpyridin-2-yl)ethanesulfonylmethyl,2-(3-phenylpyridin-2-yl)ethanesulfonylmethyl,2-(4-phenylpyridin-3-yl)ethanesulfonylmethyl,2-(3-phenylpyridin-4-yl)ethanesulfonylmethyl,6-(pyridin-2-yl)pyridin-2-ylmethanesulfonylmethyl,3-(pyridin-2-yl)pyridin-2-ylmethane-sulfonylmethyl,4-(pyridin-2-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-2-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-2-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[3-(pyridin-2-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[4-(pyridin-2-yl)pyridin-3-yl]ethanesulfonylmethyl,2-[3-(pyridin-2-yl)pyridin-4-yl]ethanesulfonylmethyl,6-(pyridin-3-yl)pyridin-2-ylmethane-sulfonylmethyl,3-(pyridin-3-yl)pyridin-2-ylmethanesulfonylmethyl,4-(pyridin-3-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-3-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-3-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[3-(pyridin-3-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[4-(pyridin-3-yl)pyridin-3-yl]ethanesulfonylmethyl,2-[3-(pyridin-3-yl)pyridin-4-yl]ethanesulfonylmethyl,6-(pyridin-4-yl)pyridin-2-ylmethanesulfonylmethyl,3-(pyridin-4-yl)pyridin-2-ylmethanesulfonylmethyl,4-(pyridin-4-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-4-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-4-yl)pyridin-2-yl]-ethanesulfonylmethyl,2-[3-(pyridin-4-yl)pyridin-2-yl]methanesulfonylmethyl,2-[4-(pyridin-4-yl)pyridin-3-yl]methanesulfonylmethyl,2-[3-(pyridin-4-yl)pyridin-4-yl]ethanesulfonylmethyl,2,2-dimethylcyclopropylmethanesulfonylmethyl,biphen-2-ylmethanesulfonylmethyl,2-thiophen-2-ylphenylmethanesulfonylmethyl,2-thiazol-2-ylphenylmethanesulfonylmethyl,2-thiazol-5-ylphenylmethanesulfonylmethyl,2-[1.2.3]thiadiazol-5-ylphenylmethane-sulfonylmethyl,2-isoxazol-5-ylphenylmethanesulfonylmethyl,2-(1-methylpyrazol-5-yl)phenyl-methanesulfonylmethyl,2-[1.2.3]triazol-5-ylphenylmethanesulfonylmethyl,2-[1.2.3]oxadiazol-5-ylphenylmethanesulfonylmethyl,2-[(1.2.3)triazol-5-yl]phenylmethanesulfonylmethyl,2-[(1.2.3)triazol-1-yl]phenylmethanesulfonylmethyl,oxazolo[5,4-b]pyridin-2-ylmethane-sulfonylmethyl,oxazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,oxazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,benzimidazol-5-ylmethanesulfonylmethyl,benzimidazol-4-ylmethanesulfonylmethyl,3H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-3H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃.3H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,1-CF₃-1H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,1-CF₃-1H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,thiazolo[5,4-b]pyridin-2-ylmethanesulfonylmethyl,thiazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,thiazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,5-CF₃thiazolo[5,4-b]pyridin-2-ylmethanesulfonylmethyl,4-CF₃-thiazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,7-CF₃-thiazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[2,3-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[3,2-c]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[3,2-b]pyridin-2-ylmethanesulfonylmethyl,imidazo[1,2-c]pyrimidin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-c]pyrimidin-2-methanesulfonylmethyl,imidazo[1,2-a]pyrimidin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-b]pyridazin-2-ylmethanesulfonylmethyl,imidazo[1,2-a]pyrazin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-a]pyrazin-2-methanesulfonylmethyl,pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,3-CF₃-pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,4-CF₃-pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,imidazo[1,2-d][1,2,4]triazin-2-methanesulfonylmethyl,3-CF₃-imidazo[1,2-d][1,2,4]triazin-2-methanesulfonylmethyl,[1,3]benzoxazol-2-ylmethanesulfonylmethyl,5-F-[1,3]benzoxazol-2-ylmethanesulfonylmethyl[1,3]benzoxazol-4-ylmethanesulfonylmethyl,2-CF₃-[1,3]benzoxazol-4-ylmethanesulfonyl-methyl,[1,3]benzoxazol-7-ylmethanesulfonylmethyl,2-CF₃-[1,3]benzoxazol-7-ylmethane-sulfonylmethyl,[1,2]benzoxazol-3-ylmethanesulfonylmethyl,[1,2]benzoxazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]benzoxazol-4-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzoxazol-4-ylmethanesulfonylmethyl,6-CF₃-[1,2]benzoxazol-7-ylmethane-sulfonylmethyl,6-CN-[1,2]benzoxazol-7-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzoxazol-7-ylmethanesulfonylmethyl,5-F-[1,2]benzoxazol-3-ylmethanesulfonylmethyl,[2,3]benzoxazol-7-ylmethanesulfonylmethyl,6-CF₃-[2,3]benzoxazol-7-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzoxazol-7-ylmethanesulfonylmethyl,5-CF₃-[2,3]benzoxazol-4-ylmethane-sulfonylmethyl,5-CN-[2,3]benzoxazol-4-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzoxazol-4-ylmethanesulfonylmethyl,benzothiazol-2-ylmethanesulfonylmethyl,5-F-benzothiazol-2-ylmethanesulfonylmethyl,benzothiazol-4-ylmethanesulfonylmethyl,2-CF₃-benzothiazol-4-ylmethanesulfonylmethyl,benzothiazol-7-ylmethanesulfonylmethyl,2-CF₃-benzothiazol-7-ylmethanesulfonylmethyl,[1,2]benzothiazol-3-ylmethanesulfonylmethyl,[1,2]benzothiazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]benzothiazol-4-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzothiazol-4-ylmethanesulfonylmethyl,6-CF₃-[1,2]benzothiazol-7-ylmethane-sulfonylmethyl,6-CN-[1,2]benzothiazol-7-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzothiazol-7-ylmethanesulfonylmethyl,5-F-[1,2]benzothiazol-3-ylmethanesulfonylmethyl,[2,3]benzothiazol-7-ylmethanesulfonylmethyl,6-CF₃-[2,3]benzothiazol-7-ylmethane-sulfonylmethyl,1-CF₃-[2,3]benzothiazol-7-ylmethanesulfonylmethyl,5-CF₃-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,5-CN-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,4-CF₃-2-CH₃-thiazol-5-ylmethanesulfonylmethyl,4-CF₃-thiazol-5-ylmethanesulfonylmethyl,4-CF₃-2-phenyl-thiazol-5-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-thiazol-4-ylmethanesulfonylmethyl,5-CF₃-thiazol-4-ylmethanesulfonylmethyl,5-CF₃-2-phenyl-thiazol-4-ylmethanesulfonylmethyl,5-CH₃-thiazol-2-ylmethanesulfonylmethyl,5-CF₃-thiazol-2-ylmethanesulfonylmethyl,5-phenyl-thiazol-2-ylmethanesulfonylmethyl,4-CH₃-thiazol-2-ylmethanesulfonylmethyl,4-CF₃-thiazol-2-ylmethanesulfonylmethyl,4-phenyl-thiazol-2-ylmethanesulfonylmethyl,5-CH₃-2-(pyridin-2-yl)-[1,2,3]triazol-4-ylmethanesulfonylmethyl,5-CF₃-2-(pyridin-2-yl)-[1,2,3]triazol-4-ylmethanesulfonylmethyl,5-CF₃-2-(4-methylsulfonylphenyl)-[1,2,3]triazol-4-ylmethane-sulfonylmethyl,4,5-dimethyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CF₃-4-CH₃-[1,2,4]triazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,5-CF₃-4-cyclopropyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,2,5-dimethyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,2-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,2-cyclopropyl-5-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CF₃-1-CH₃-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,1-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CH₃-1-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,3-CH₃-[1,2,4]oxadiazol-5-ylmethanesulfonylmethyl3-CF₃-[1,2,4]oxadiazol-5-ylmethanesulfonylmethyl,3-phenyl-[1,2,4]oxadiazol-5-ylmethane-sulfonylmethyl,5-CH₃-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,5-CF₃-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,5-phenyl-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,2-CH₃-[1,3,4]oxadiazol-5-ylmethanesulfonylmethyl,2-CF₃-[1,3,4]oxadiazol-5-ylmethane-sulfonylmethyl,2-phenyl-[1,3,4]oxadiazol-5-ylmethanesulfonylmethyl,3-CH₃-[1,2,4]thiadiazol-5-ylmethanesulfonylmethyl,3-CF₃-[1,2,4]thiadiazol-5-ylmethanesulfonylmethyl,3-phenyl-[1,2,4]thiadiazol-5-ylmethanesulfonylmethyl,5-CH₃-[1,2,4]thiadiazol-3-ylmethane-sulfonylmethyl,5-CF₃-[1,2,4]thiadiazol-3-ylmethanesulfonylmethyl,5-phenyl-[1,2,4]thiadiazol-3-ylmethanesulfonylmethyl,2-CH₃-[1,3,4]thiadiazol-5-ylmethanesulfonylmethyl,2-CF₃-[1,3,4]thiadiazol-5-ylmethanesulfonylmethyl,2-phenyl-[1,3,4]thiadiazol-5-ylmethane-sulfonylmethyl,2,2-difluoropyrrolidinylmethanesulfonylmethyl,3,3-difluoropyrrolidinyl-methanesulfonylmethyl,3-CF₃—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,3-CN—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-CF₃—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-(1-CH₃-1-hydroxyethyl)-N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,1,3-dimethylpyrrol-2-ylmethane-sulfonylmethyl,4-CF₃—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,4-CN—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,4-CN—N-(3,3,3-trifluoropropyl)-pyrrol-3-ylmethanesulfonylmethyl,2-CF₃—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,2-CF₃—N-phenyl-pyrrol-3-ylmethane-sulfonylmethyl,4-CF₃-pyrrol-2-ylmethanesulfonylmethyl,4-(1-CH₃-1-hydroxyethyl)-pyrrol-2-ylmethanesulfonylmethyl,3-CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-CF₃-pyrrol-3-ylmethane-sulfonylmethyl,2-CF₃-pyrrol-3-ylmethanesulfonylmethyl,3-CF₃-pyrrol-2-ylmethane-sulfonylmethyl,2-CF₃-pyrrol-4-ylmethanesulfonylmethyl,2-CF₃—N—CH₃-pyrrol-4-ylmethane-sulfonylmethyl,3-CF₃-fur-2-ylmethanesulfonylmethyl, 3-CN-fur-2-ylmethanesulfonylmethyl,3-CF₃-fur-4-ylmethanesulfonylmethyl, 3-CN-fur-4-ylmethanesulfonylmethyl,2-CF₃-fur-3-ylmethanesulfonylmethyl,3-CF₃-thiazol-2-ylmethanesulfonylmethyl,3-CN-thiazol-2-ylmethanesulfonylmethyl,3-CF₃-thiazol-4-ylmethanesulfonylmethyl,3-CN-thiazol-4-ylmethanesulfonylmethyl,2-CF₃-thiazol-3-ylmethanesulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-5-ylmethanesulfonylmethyl,N—CH₃-3-(1-CH₃-1-hydroxyethyl)-1H-pyrazol-5-ylmethane-sulfonylmethyl,N—CH₃-3-phenyl-1H-pyrazol-5-ylmethanesulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,N—CH₃-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl,N-phenyl-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl,N-phenyl-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,N-phenyl-5-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,(N—CH₃-4-CF₃-1H-imidazol-2-ylmethane)-sulfonylmethyl,[N—CH₃-4-(1-CH₃-1-hydroxyethyl)-1H-imidazol-2-ylmethane]-sulfonylmethyl,(N—CH₃-4-phenyl-1H-imidazol-2-ylmethane)-sulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,(N—CH₃-2-CF₃-1H-imidazol-5-ylmethane)-sulfonylmethyl,(N—CH₃-2-phenyl-1H-imidazol-5-ylmethane)-sulfonylmethyl,(N—CH₃-5-CF₃-1H-imidazol-4-ylmethane)-sulfonylmethyl,(N-phenyl-5-CF₃-1H-imidazol-4-ylmethane)-sulfonylmethyl,4-CN-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CN-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CN-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CN-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CN-isothiazol-5-ylmethanesulfonylmethyl,4-CN-3-phenyl-isothiazol-5-ylmethanesulfonylmethyl,4-CN-isothiazol-3-ylmethanesulfonylmethyl,4-CN-5-phenyl-isothiazol-3-ylmethane-sulfonylmethyl,4-CF₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl.3-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,3-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CH₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,3-CH₃-[1,2]oxazol-4-ylmethane-sulfonylmethyl,5-CH₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CH₃-isothiazol-5-ylmethane-sulfonylmethyl,4-CH₃-3-phenyl-isothiazol-5-ylmethanesulfonylmethyl,4-CH₃-isothiazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-isothiazol-3-ylmethanesulfonylmethyl,3-CH₃-isothiazol-4-ylmethanesulfonylmethyl,5-CH₃-isothiazol-4-ylmethanesulfonylmethyl,4-CF₃-2-CH₃-[1,3]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,3]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-2-phenyl-[1,3]oxazol-5-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-[1,3]oxazol-4-yl-methanesulfonylmethyl,5-CF₃-[1,3]oxazol-4-ylmethanesulfonylmethyl,5-CF₃-2-phenyl-[1,3]oxazol-4-ylmethanesulfonylmethyl,5-CH₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,5-CF₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,5-phenyl-[1,3]oxazol-2-ylmethane-sulfonylmethyl,4-CH₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,4-CF₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,4-phenyl-[1,3]oxazol-2-ylmethanesulfonylmethyl,N-methyl-indol-2-ylmethanesulfonylmethyl,3-CF₃-indol-2-ylmethanesulfonylmethyl,3-CF₃—N-methyl-indol-2-ylmethanesulfonylmethyl,5-fluoro-N-methyl-indol-2-ylmethanesulfonylmethyl,N-methyl-indol-3-ylmethanesulfonylmethyl,2-CF₃-indol-3-ylmethanesulfonylmethyl,2-CF₃—N-methyl-indol-3-ylmethanesulfonylmethyl,5-fluoro-N-methyl-indol-3-ylmethanesulfonylmethyl,5-CF₃—N-methyl-indol-4-ylmethanesulfonylmethyl,5-CN—N-methyl-indol-4-ylmethane-sulfonylmethyl,2-CF₃—N-methyl-indol-4-ylmethanesulfonylmethyl,3-CF₃—N-methyl-indol-4-ylmethanesulfonylmethyl,6-CF₃—N-methyl-indol-7-ylmethanesulfonylmethyl,6-CN—N-methyl-indol-7-ylmethanesulfonylmethyl,2-CF₃—N-methyl-indol-7-ylmethanesulfonylmethyl,3-CF₃—N-methyl-indol-7-ylmethanesulfonylmethyl,benzofuran-2-ylmethanesulfonylmethyl,3-CF₃-benzofuran-2-ylmethanesulfonylmethyl,3-CN-benzofuran-2-ylmethanesulfonylmethyl,5-F-benzofuran-2-ylmethanesulfonylmethyl,benzofuran-3-ylmethanesulfonylmethyl,2-CF₃-benzofuran-3-ylmethanesulfonylmethyl,2-CH₃-benzofuran-3-ylmethanesulfonylmethyl,5-F-benzofuran-3-ylmethanesulfonylmethyl,5-CF₃-benzofuran-4-ylmethanesulfonylmethyl,5-CN-benzofuran-4-ylmethanesulfonylmethyl,2-CF₃-benzofuran-4-ylmethanesulfonylmethyl,3-CF₃-benzofuran-4-ylmethanesulfonylmethyl,6-CF₃-benzofuran-7-ylmethanesulfonylmethyl,6-CN-benzofuran-7-ylmethanesulfonylmethyl,2-CF₃-benzofuran-7-ylmethanesulfonylmethyl,3-CF₃-benzofuran-7-ylmethanesulfonylmethyl,benzothien-2-ylmethanesulfonylmethyl,(3-CF₃-benzothien-2-ylmethane)-sulfonylmethyl,(3-CN-benzothien-2-ylmethane)-sulfonylmethyl,(5-F-benzothien-2-ylmethane)-sulfonylmethyl,benzothien-3-ylmethanesulfonylmethyl,(2-CF₃-benzothien-3-ylmethane)-sulfonylmethyl,(2-CH₃-benzothien-3-ylmethane)-sulfonylmethyl,(5-fluoro-benzothien-3-ylmethane)-sulfonylmethyl,(5-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(5-CN-benzothien-4-ylmethane)-sulfonylmethyl,(2-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(3-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(6-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,(6-CN-benzothien-7-ylmethane)-sulfonylmethyl,(2-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,(3-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,N-methyl-benzimidazol-2-ylmethanesulfonylmethyl,(5-fluoro-N-methyl-benzimidazol-2-ylmethane)-sulfonylmethyl,(N-methyl-indazol-3-ylmethane)-sulfonylmethyl,(5-fluoro-N-methyl-indazol-3-ylmethane)-sulfonylmethyl,(2-CF₃—N-methyl-benzimidazol-4-ylmethane)-sulfonylmethyl,(2-CF₃—N-methyl-benzimidazol-7-ylmethane)-sulfonylmethyl,(N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(5-CF₃—N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(3-CF₃—N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(6-CF₃—N-methyl-indazol-7-ylmethane)-sulfonylmethyl,(6-CN—N-methyl-indazol-7-ylmethane)-sulfonylmethyl, or(3-CF₃—N-methyl-indazol-7-ylmethane)-sulfonylmethyl.

(i) Within this group (G), a preferred group of compounds is thatwherein:

R⁴ is hydrogen; and

R^(4′) is 1,1,2,2-tetrafluoroethyl or 1,1,2,2,2-pentafluoroethyl.

(ii) Within this group (G), another preferred group of compounds is thatwherein:

R^(4′) is difluoromethyl or trifluoromethyl; and

R⁴ is phenyl, 2-fluorophenyl, or 2,4-difluorophenyl.

(iii) Within this group (G), yet another preferred group of compounds isthat wherein:

R⁴ is difluoromethyl or trifluoromethyl; and

R^(4′) is 1,1,2,2-tetrafluoroethyl or 1,1,2,2,2-pentalluoroethyl.

(iv) Within this group (G), yet another preferred group of compounds isthat wherein:

R⁴ is methyl or ethyl; and

R^(4′) is 1,1,2,2-tetrafluoroethyl or 1,1,2,2,2-pentafluoroethyl.

Within the above preferred group (G), G(i), G(ii), G(iii) and G(iv), aparticularly preferred group of compounds is that wherein R¹ and R²together with the carbon atom to which they are attached formcycloalkylene, preferably R¹ and R² together with the carbon atom towhich they are attached form cyclopropylene.

Within the above preferred group (G), G(i), G(ii), G(iii) and G(iv),another particularly preferred group of compounds is that wherein R¹ andR² together with the carbon atom to which they are attached formpiperidin-4-yl substituted at the nitrogen with ethyl, trifluoroethyl orcyclopropyl.

Within the above preferred group (G), G(i), G(ii), G(iii) and G(iv), yetanother particularly preferred group of compounds is that wherein R¹ andR² together with the carbon atom to which they are attached formtetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or1,1-dioxohexahydrothiopyran-4-yl.

Reference to the preferred embodiments set forth above is meant toinclude all combinations of particular and preferred groups unlessstated otherwise.

Compounds of Formula (I) where R¹ and R² together form cyclopropyleneand R³, R⁴, and R^(4′) are as defined in Table I below are:

TABLE I Stereochem at Cpd # (*C, **C) R^(4′) R³ R⁴ 1 (S, R) CF₃4-CF₃-pyridin-3-ylmethanesulfonylmethyl 4-Fphenyl 2 (S, R) CF₃pyridin-3-ylmethanesulfonylmethyl 4-F-phenyl 3 (S, R) CF₃pyridazin-3-ylmethanesulfonylmethyl 4-F-phenyl 4 (S, R) CF₃2-CF₃-furan-5-ylmethanesulfonylmethyl 4-F-phenyl 5 (S, R) CF₃pyrimidin-5-ylmethanesulfonylmethyl 4-F-phenyl 6 (S, R) CF₃2-CH₃-thiazol-4-ylmethanesulfonylmethyl 4-F-phenyl 7 (S, R) CF₃pyridin-4-ylmethanesulfonylmethyl 4-F-phenyl 8 (S, R) CF₃pyrimidin-4-ylmethanesulfonylmethyl 4-F-phenyl 9 (S, R) CF₃2-(1-oxopyrrol-1-yl)ethanesulfonylmethyl 4-F-phenyl 10 (R, R) CF₃pyridin-3-ylmethanesulfonylmethyl 4-F-phenyl 11 (S, R) CF₃cyclopropylmethanesulfonylmethyl 3-F-phenyl 12 (S, R) CF₃3,3,3-trifluoropropane-1-sulfonylmethyl 4-F-phenyl 13 (S, R) CF₃2-CF₃-pyridin-5-ylmethanesulfonylmethyl 4-F-phenyl 14 (S, R) CF₃4-[1.2.4]-triazol-1-ylphenylmethane-sulfonylmethyl 4-F-phenyl 15 (S, R)CF₃ 2-(2-oxo-2,3-dihydrobenzimidazol-1-yl)- 4-F-phenylethanesulfonylmethyl 16 (S, R) CF₃5-oxopyrrolidin-2-ylmethanesulfonylmethyl 4-F-phenyl 17 (S, R) CF₃2-F-pyridin-3-ylmethanesulfonylmethyl 4-F-phenyl 18 (S, R) CF₃3-CH₃-oxetan-3-ylmethanesulfonylmethyl 4-F-phenyl 19 (S, R) CF₃2-phenylethanesulfonylmethyl 4-F-phenyl 20 (R, R) CF₃3,3,3-trifluoropropane-1-sulfonylmethyl 4-F-phenyl 21 (S, R) CF₃fluoro-pyridin-2-ylmethanesulfonylmethyl 4-F-phenyl 22 (S, R) CF₃fluoro-pyrazin-2-ylmethanesulfonylmethyl 4-F-phenyl 23 (S, R) CF₃difluoro-pyridin-2-ylmethanesulfonylmethyl 4-F-phenyl 24 (S, R) CF₃difluoro-pyridin-3-ylmethanesulfonylmethyl 4-F-phenyl 25 (S, R) CF₃quinolin-2-ylmethanesulfonylmethyl 4-F-phenyl 26 (S, R) CF₃benzo[1.2.5]thiadiazol-4-yl-methanesulfonylmethyl 4-F-phenyl 27 (S, R)CF₃ benzothiazol-2-ylmethanesulfonylmethyl 4-F-phenyl 28 (S, R) CF₃5-methylisoxazol-3-ylmethanesulfonylmethyl 4-F-phenyl 29 (S, R) CF₃2-methylpropylsulfonylmethyl 4-F-phenyl 30 (S, R) CF₃cyclobutylmethanesulfonylmethyl 4-F-phenyl 31 (S, R) CF₃2,6-difluorophenylmethanesulfonylmethyl 4-F-phenyl 32 (S, R) CF₃2,4-difluorophenylmethanesulfonylmethyl 4-F-phenyl 33 (S, R) CF₃quinolin-3-ylmethanesulfonylmethyl 4-F-phenyl 34 (S, R) CF₃4,4,4-trifluorobutyl-1-sulfonylmethyl 4-F-phenyl 35 (S, R) CF₃2-CF₃-phenylmethanesulfonylmethyl 4-F-phenyl 36 (S, R) CF₃2-CF₃O-phenylmethanesulfonylmethyl 4-F-phenyl 37 (S, R) CF₃cyclopropylmethanesulfonylmethyl 3,5-diF- phenyl 38 (S, R) CF₃cyclopropylmethanesulfonylmethyl 2,5-diF- phenyl 39 (S, R) CF₃2-pyridin-2-ylethanesulfonylmethyl 4-F-phenyl 40 (S, R) CF₃2-pyridin-3-ylethanesulfonylmethyl 4-F-phenyl 41 (S, R) CF₃quinolin-8-ylmethanesulfonylmethyl 4-F-phenyl 42 (S, R) CF₃cyclopropylmethanesulfonylmethyl 2,3-diF- phenyl 43 (S, R) CF₃cyclopropylmethanesulfonylmethyl 2,4-diF- phenyl 44 (S, R) CF₃5-methyl-3-phenylisoxazol-4-yl- 4-F-phenyl methanesulfonylmethyl 45 (S,R) CF₃ 4-methyl-2-phenyl-[1.2.3]triazol-5-ylmethane- 4-F-phenylsulfonylmethyl 46 (S, R) CF₃ 2-cyanophenylmethanesulfonylmethyl4-F-phenyl 47 (S, R) CF₃ 3-methoxycarbonylphenylmethanesulfonylmethyl4-F-phenyl 48 (S, R) CHF₂ cyclopropylmethanesulfonylmethyl 4-F-phenyl 49(RS, R) CF₃ cyclopropylmethanesulfonylmethyl 2-Cl-pyridin- 5-yl 50 (S,R) CF₂C pyridin-2-ylmethanesulfonylmethyl 4-F-phenyl F₃ 51 (S, R) CF₂C1-oxopyridin-2-ylmethanesulfonylmethyl 4-F-phenyl F₃ 52 (S, R) CF₂Cpyridin-3-ylmethanesulfonylmethyl 4-F-phenyl F₃ 53 (S, R) CF₂C1-oxopyridin-3-ylmethanesulfonylmethyl 4-F-phenyl F₃ 54 (S, R) CF₂Ccyclopropylmethanesulfonylmethyl 4-F-phenyl F₃ 55 (S, R) CF₃quinoxalin-2-ylmethanesulfonylmethyl 4-F-phenyl 56 (S, R) CF₃tetrahydropyran-2(RS)-ylmethanesulfonylmethyl 4-F-phenyl 57 (S, R) CF₃2,6-dichlorophenylmethanesulfonylmethyl 4-F-phenyl 58 (S, R) CF₃3-methoxycarbonylfuran-2-yl- 4-F-phenyl methanesulfonylmethyl 59 (S, R)CF₂C 5-methylisoxazol-3-ylmethanesulfonylmethyl 4-F-phenyl F₃ 60 (S, R)CF₃ 2,2-dimethylpropylsulfonylmethyl 4-F-phenyl 61 (R, R) CF₂Cpyridin-3-ylmethanesulfonylmethyl 4-F-phenyl F₃ 62 (S, R) CF₃ethanesulfonylmethyl 4-F-phenyl 63 (R, R) CF₃cyclopropylmethanesulfonylmethyl 2,5-diF- phenyl 64 (S, R) CF₃cyclopropylmethanesulfonylmethyl 2,6-diF- phenyl 65 (R, R) CF₃cyclopropylmethanesulfonylmethyl 2,6-diF- phenyl 66 (R, R) CF₃cyclopropylmethanesulfonylmethyl 2,3-diF- phenyl 67 (R, R) CF₃cyclopropylmethanesulfonylmethyl 2,4-diF- phenyl 68 (S, R) CF₃methanesulfonylmethyl 4-F-phenyl 69 (S, R) CF₃ propane-1-sulfonylmethyl4-F-phenyl 70 (S, R) CF₃ 1H-indol-2-ylmethanesulfonylmethyl 4-F-phenyl71 (S, R) CF₃ cyclopropylmethanesulfonylmethyl 2-F-phenyl 72 (R, R) CF₃cyclopropylmethanesulfonylmethyl 2-F-phenyl 73 (S, R) CF₃pyridin-2-ylmethanesulfonylmethyl 3,4-diF- phenyl 74 (S, R) CF₃pyridin-3-ylmethanesulfonylmethyl 3,4-di- Fphenyl 75 (S, R) CF₃2-(1H-indol-3-yl)ethanesulfonylmethyl 4-F-phenyl 76 (S, R) CF₃tetrahydropyran-4-ylmethanesulfonylmethyl 4-F-phenyl 77 (S, R) CF₃1-oxopyridin-2-ylmethanesulfonylmethyl 2-F-phenyl 78 (R, R) CF₃1-oxopyridin-2-ylmethanesulfonylmethyl 2-F-phenyl 79 (S, R) CF₃pyridin-2-ylmethanesulfonylmethyl 2-F-phenyl 80 (R, R) CF₃pyridin-2-ylmethanesulfonylmethyl 2-F-phenyl 81 (S, R) CF₃cyclopropylmethanesulfonylmethyl 2,3,4-triF- phenyl 82 (R, R) CF₃cyclopropylmethanesulfonylmethyl 2,3,4-triF- phenyl 83 (S, R) CF₃2,2,2-trifluoroethanesulfonylmethyl 2-F-phenyl 84 (S, R) CF₃benzisoxazol-3-ylmethanesulfonylmethyl 2-F-phenyl 85 (RS, R) CF₃cyclopropylmethanesulfonylmethyl 3-OH-6-CH₃- pyridin-2-yl 86 (S, R) CF₃2-tert-butyl-[1.3.4]thiadiazol-5-ylmethane- 4-F-phenyl sulfonylmethyl 87(S, R) CF₃ 2,4,6-trifluorophenylmethanesulfonylmethyl 4-F-phenyl 88 (S,R) CF₂C 2-pyridin-2-ylethanesulfonylmethyl 4-F-phenyl F₃ 89 (S, R) CF₃1-ethyl-2,5-dioxopyrrolidin-3-ylmethane- 4-F-phenyl sulfonylmethyl 90(S, R) CF₃ benzisoxazol-3-ylmethanesulfonylmethyl 4-F-phenyl 91 (S, R)CF₃ cyclopropylmethanesulfonylmethyl 2,4,5-triF- phenyl 92 (S, S) CF₃2-cyclopropylmethylsulfonylethyl 4-F-phenyl 93 (S, S) CF₃2-methylsulfonylethyl 4-F-phenyl 94 (S, S) CF₃ 2-phenylsulfonylethyl4-F-phenyl 95 (S, S) CF₃ 2-(4-trifluoromethylphenylsulfonyl)ethyl4-F-phenyl 96 (S, S) CF₃ 2-(4-methylsulfonylphenylsulfonyl)ethyl4-F-phenyl 97 (S, R) CF₃ butylsulfonylmethyl 4-F-phenyl 98 (S, R) CF₃pentylsulfonylmethyl 4-F-phenyl 99 (S, R) CF₃ hexylsulfonylmethyl4-F-phenyl 100 (S, R) CF₃ heptylsulfonylmethyl 4-F-phenyl 101 (S, R) CF₃3-phenylisooxazol-5-ylmethylsulfonylmethyl 4-F-phenyl 102 (S, R) CF₃5-phenyloxazol-4-ylmethylsulfonylmethyl 4-F-phenyl 103 (S, R) CF₃[1,2,4]oxadiaxol-3-ylmethylsulfonylmethyl 4-F-phenyl 104 (S, R) CF₃5-phenyl[1,2,4]oxadiaxol-3-ylmethylsulfonylmethyl 4-F-phenyl 105 (S, R)CF₃ 5-thiophen-2-yl[1,2,4]oxadiaxol-3- 4-F-phenyl ylmethylsulfonylmethyl106 (S, R) CF₃ 3-thiophen-5-yl[1,2,4]oxadiaxol-3- 4-F-phenylylmethylsulfonylmethyl 107 (S, R) CF₃3,5-dimethylisooxadiaxol-4-ylmethylsulfonylmethyl 4-F-phenyl 108 (S, R)CF₃ 6-methylpyridin-2-ylmethylsulfonylmethyl 4-F-phenyl 109 (S, R) CF₃3-trifluoromethyl-pyridin-4- 4-F-phenyl ylmethanesulfonylmethyl 110 (S,R) CF₃ cyclopropylmethylsulfonylmethyl 2,4,6-triF- phenyl 111 (R, R) CF₃cyclopropylmethylsulfonylmethyl 2,4,6-triF- phenyl 112 (R) CF₂Ccyclopropylmethylsulfonylmethyl hydrogen HF₂ 113 (RS, R) CF₂C3-trifluorobenzylsulfonylmethyl 2,4-diF- HF₂ phenyl 114 (S, R) CF₂C3-trifluorobenzylsulfonylmethyl 2,4-diF- HF₂ phenyl 115 (S, R) CF₃2-(2-oxoindol-1-yl)ethylsulfonylmethyl 4-F-phenyl 116 (S, R) CF₃2-(2,3-dioxoindol-1-yl)ethylsulfonylmethyl 4-F-phenyl 117 (S, R) CF₃4-methylsulfonylbenzylsulfonylmethyl 2,4-diF- phenyl 118 (S, R) CF₃3-methylsulfonylbenzylsulfonylmethyl 2,4-diF- phenyl 119 (R, R) CF₃3-methylsulfonylbenzylsulfonylmethyl 2,4-diF- phenyl 120 (R, R) CF₃2-cyanobenzylsulfonylmethyl 2,4-diF- phenyl 121 (S, R) CF₃2-cyanobenzylsulfonylmethyl 2,4-diF- phenyl 122 (S, R) CF₃2-methylsulfonylbenzylsulfonylmethyl 2,4-diF- phenyl 123 (R, R) CF₃2-methylsulfonylbenzylsulfonylmethyl 2,4-diF- phenyl 124 (R, R) CF₃4-methylsulfonylbenzylsulfonylmethyl 2,4-diF- phenyl 125 (S, R) CF₃4-trifluoromethylpyridin-3-ylsulfonylmethyl 2,4-diF- phenyl 126 (R, R)CF₃ 2-trifluoromethylbenzylsulfonylmethyl 2,4-diF- phenyl 127 (S, R) CF₃2-trifluoromethylbenzylsulfonylmethyl 2,4-diF- phenyl 128 (S, R) CF₃phenylsulfonylmethyl 4-F-phenyl 129 (S, R) CF₃2-methylsulfonylbenzylsulfonylmethyl 4-F-phenyl 130 (S, R) CF₃4-methylsulfonylbenzylsulfonylmethyl 4-F-phenyl 131 (S, R) CF₃3-methylsulfonylbenzylsulfonylmethyl 4-F-phenyl 132 (S, R) CF₃2-(2-oxo-imidazolidin-1-yl)-ethanesulfonylmethyl 4-F-phenyl 133 (S, R)CF₃ 2-(2-oxo-imidazolidin-1-yl)-ethanesulfonylmethyl 2,4-diF- phenyl 134(S, R) CF₃ 2-[4-(4-fluorophenyl)-2-trifluoromethyl-imidazol-1- 2,4-diF-yl]-ethanesulfonylmethyl phenyl 135 (S, R) CF₃2-[4-(4-fluorophenyl)-2-trifluoromethyl-imidazol-1- 4-F-phenylyl]-ethanesulfonylmethyl 136 (S, R) CF₃2-[5-(4-fluorophenyl)-2-trifluoromethyl-imidazol-1- 4-F-phenylyl]-ethanesulfonylmethyl 137 (S, R) CF₃ 2-(2-trifluoromethylimidazol-1-4-F-phenyl yl)ethanesulfonylmethyl 138 (S, R) CF₃2-(2-trifluoromethylimidazol-1- 2,4-diF- yl)ethanesulfonylmethyl phenyl139 (S, R) CF₃ cyclopropylmethylsulfonylmethyl tetrahydropy- ran-4-yl140 (S, R) CF₃ 2-(2-oxo-pyrrolidin-1-yl)-ethanesulfonylmethyl 4-F-phenyl141 (S, R) CF₃ 2-(4-oxo-5-aza-benzospiro[2.4]hept-6-en-5-yl)- 4-F-phenylethanesulfonylmethyl 142 (S, R) CF₃ cyclopropylmethylsulfonylmethyl4-Cl-phenyland compounds of Formula (I) R¹, R², R³, R⁴ and R^(4′) are as defined inTable II below are:

TABLE II Cpd Stereochem # at (*C, **C) R¹ and R² R^(4') R³ R⁴ 143 (S, R)cyclopentylene CF₃ pyridine-3-ylmethanesulfonylmethyl 4-Fphenyl 144 (S,R) cyclobutylene CF₃ pyridine-3-ylmethanesulfonylmethyl 4-Fphenyl 145(S, R) CH₃ and CH₃ CF₃ pyridine-3-ylmethanesulfonylmethyl 4-Fphenyl 146(S, R) cyclobutylene CF₃ cyclopropylmethanesulfonylmethyl 4-Fphenyl 147(S, R) CH₃ and CH₃ CF₃ 4-trifluoromethylpyridin-3- 4-Fphenylylmethanesulfonylmethyland are named:

-   N-(1-cyanocyclopropyl)-3-(4-trifluoromethylpyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-pyridin-3-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-pyridan-3-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2-trifluoromethylfuran-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-pyrimidin-5-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2-methylthiazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-pyridin-4-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-pyrimidin-4-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-[2-(1-oxopyrrol-1-ylmethanesulfonyl]-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-pyridin-3-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-3-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(3,3,3-trifluoropropane-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2-trifluoromethylpyridin-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(4-[1.2.4]-triazol-1-ylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-[2-(2-oxo-2,3-dihydrobenzimidazol-1-ethanesulfonyl]-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(5-oxo-pyrrolidin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylaminopropionamide;-   N-(1-cyanocyclopropyl)-3-(2-fluoropyridin-3-ylmethanesulfonyll)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylaminopropionamide;-   N-(1-cyanocyclopropyl)-3-(3-methyloxetan-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2-phenylethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(3,3,3-trifluoropropane-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(fluoropyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(fluoropyrazin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(difluoropyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(difluoropyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(quinolin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(benzo[1.2.5]thiadiazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide    ;-   N-(1-cyanocyclopropyl)-3-(benzothiazol-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide    ;-   N-(1-cyanocyclopropyl)-3-(5-methylisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2-methylpropylsulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclobutylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2,6-difluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2,4-difluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(quinolin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(4,4,4-trifluorobutyl-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2-trifluoromethylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(2-trifluoromethoxyphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,5-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,5-difluorophenylethylamino)propionamide    ;-   N-(1-cyanocyclopropyl)-3-(2-pyridin-2-ylethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2-pyridin-3-ylethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(quinolin-8-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,3-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,4-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(5-methyl-3-phenylisoxazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(4-methyl-2-phenyl-[1.2.3]triazol-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(2-cyanophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(3-methoxycarbonylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2-difluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(RS)-2-chloropyridin-5-ylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(1-oxopyridin-3-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(quinoxalin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(tetrahydropyran-2RS-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(2,6-dichlorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(3-methoxycarbonylfuran-2RS-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(5-methylisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)-propionamide;-   N-(1-cyanocyclopropyl)-3-(2,2-dimethylpropylsulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(R)-4-fluorophenylpropylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(ethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2    (R)-(2,2,2-trifluoro-1(R)-2,5-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,6-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,6-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,3-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,4-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(methanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(propane-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(1H-indol-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,4-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,4-difluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-[2-(1H-indol-3-ylmethanesulfonyl]-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(tetrahydropyran-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,3,4-trifluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,3,4-trifluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2,2,2-trifluoroethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(benzisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;-   N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(RS)-(3-hydroxy-6-methyl-pyridin-2-yl)-ethylamino]-propionamide;-   N-(1-cyanocyclopropyl)-3-(2-tert-butyl-[1.3.4]-thiadiazol-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2,4,6-trifluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(2-pyridin-2-ylethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(1-ethyl-2,5-dioxopyrrolidin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;-   N-(1-cyanocyclopropyl)-3-(benzisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;-   N-(1-cyano-cyclopropyl)-4-cyclopropylmethanesulfonyl-2(S)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-butyramide;-   N-(1-cyano-cyclopropyl)-4-methanesulfonyl-2(S)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-butyramide;-   4-benzenesulfonyl-N-(1-cyano-cyclopropyl)-2(S)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-butyramide;-   N-(1-cyano-cyclopropyl)-2(S)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-4-(4-trifluoromethyl-benzenesulfonyl)-butyramide;-   N-(1-cyano-cyclopropyl)-4-(4-methanesulfonyl-benzenesulfonyl)-2(S)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-butyramide;-   3-(butane-1-sulfonyl)-N-(1-cyano-cyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(pentane-1-sulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(hexane-1-sulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(heptane-1-sulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(3-phenyl-isoxazol-5-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(5-phenyl-oxazol-4-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-([1,2,4]oxadiazol-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(5-phenyl-[1,2,4]oxadiazol-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenye-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(3-thiophen-2-yl-[1,2,4]oxadiazol-5-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(3,5-dimethyl-isoxazol-4-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(6-methyl-pyridin-2-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(S)-(2,4,6-trifluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(R)-(2,4,6-trifluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,3,3-tetrafluoro-propylamino)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1-(2,4-difluoro-phenyl)-2,2,3,3,3-pentafluoro-propylamino]-3-(2-trifluoromethyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(5)-(2,4-difluoro-phenyl)-2,2,3,3,3-pentafluoro-propylamino]-3-(2-trifluoromethyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-3-[2-(2-oxo-2,3-dihydro-indol-1-yl)-ethanesulfonyl]-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-[2-(2,3-dioxo-2,3-dihydro-indol-1-yl)-ethanesulfonyl]-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(S)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(4-methanesulfonyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(S)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(3-methanesulfonyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(R)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(3-methanesulfonyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-3-(2-cyano-phenylmethanesulfonyl)-2(R)-[1(R)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(2-cyano-phenylmethanesulfonyl)-2(R)-[1(S)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(S)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(2-methanesulfonyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(R)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(2-methanesulfonyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(R)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(4-methanesulfonyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(5)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(4-trifluoromethyl-pyridin-3-ylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(R)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(2-trifluoromethyl-phenylmethanesulfonyl)-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(S)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-(2-trifluoromethyl-phenylmethanesulfonyl)-propionamide;-   3-benzenesulfonyl-N-(1-cyano-cyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(2-methanesulfonyl-phenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-(S)1-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(4-methanesulfonyl-phenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-(3-methanesulfonyl-phenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(R)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-[2-(2-oxo-imidazolidin-1-yl)-ethanesulfonyl]-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(S)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-[2-(2-oxo-imidazolidin-1-yl)-ethanesulfonyl]-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(S)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-{2-[4-(4-fluoro-phenyl)-2-trifluoromethyl-imidazol-1-yl]-ethanesulfonyl}-propionamide;-   N-(1-cyano-cyclopropyl)-3-{2-[4-(4-fluoro-phenyl)-2-trifluoromethyl-imidazol-1-yl]-ethanesulfonyl}-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-{2-[5-(4-fluoro-phenyl)-2-trifluoromethyl-imidazol-1-yl]-ethanesulfonyl}-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-3-[2-(2-trifluoromethyl-benzoimidazol-1-yl)-ethanesulfonyl]-propionamide;-   N-(1-cyano-cyclopropyl)-2(R)-[1(5)-(2,4-difluoro-phenyl)-2,2,2-trifluoro-ethylamino]-3-[2-(2-trifluoromethyl-benzoimidazol-1-yl)-ethanesulfonyl]-propionamide;-   N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1-(tetrahydro-pyran-4-yl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethanesulfonyl]-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclopropyl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethanesulfonyl]-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;

2(R)-[1(S)-(4-chloro-phenyl)-2,2,2-trifluoro-ethylamino]-N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-propionamide;

-   N-(1-cyano-cyclopentyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclobutyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(cyano-dimethyl-methyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;-   N-(1-cyano-cyclobutyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide;    and-   N-(cyano-dimethyl-methyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-3-(4-trifluoromethyl-pyridin-3-ylmethanesulfonyl)-propionamide.

General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisinvention can be synthesized, and various modifications to these schemescan be made and will be suggested to one skilled in the art havingreferred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., more preferably from about 0° C. to about 125° C.and most preferably at about room (or ambient) temperature, e.g., about20° C.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1999.

Compounds of Formula (I) where R¹, R², R³, R⁴ and R^(4′) are as definedin the Summary of the Invention can be prepared by proceeding as inReaction Scheme 1 below.

Reaction of a ketone of formula 1 where R⁴ and R^(4′) are as defined inthe Summary of the Invention with an α-amino ester of formula 2 where Ris a carboxy protecting group, preferably an alkyl group, preferablymethyl, and R³ is as defined in the Summary of the Invention underreductive amination reaction conditions provide a compound of formula 3.The reaction is carried out in the presence of a suitable dehydratingagent such as TiCl₄, and the like, in the presence of a base such asdiisopropylethylamine, pyridine, and the like and in a suitable organicsolvent such as methylene chloride to give an imine. The imine isreduced with a suitable reducing agent such as sodium borohydride,sodium cyanoborohydride, and the like in a suitable organic solvent suchas methanol, ethanol, and the like.

Compounds of formula 1 such as 2,2,2-trifluoromethylacetophenone and2,2,2,4′-tetrafluoroacetophenone commercially available. Others can beprepared by methods well known in the art. α-Amino esters of formula 2can be prepared by methods well known in the art.

Hydrolysis of the ester group in compound 3 provides a compound offormula 4. The hydrolysis conditions depend on the nature of theprotecting group. For example, when R is alkyl the hydrolysis is carriedout under aqueous basic hydrolysis reaction conditions to give thecorresponding acid of formula 4. The reaction is typically carried outwith cesium carbonate, lithium hydroxide, and the like in an aqueousalcohol such as methanol, ethanol, and the like.

Compound 4 is then reacted with an α-aminoacetonitrile of formula 5 togive a compound of Formula (I). The reaction is typically carried out inthe presence of a suitable coupling agent e.g.,benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate(PyBOP®), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HBTU),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or1,3-dicyclohexyl-carbodiimide (DCC), optionally in the presence of1-hydroxybenzotriazole (HOBT), and a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and thelike. The reaction is typically carried out at 20 to 30° C., preferablyat about 25° C., and requires 2 to 24 h to complete. Suitable reactionsolvents are inert organic solvents such as halogenated organic solvents(e.g., methylene chloride, chloroform, and the like), acetonitrile,N,N-dimethylformamide, ethereal solvents such as tetrahydrofuran,dioxane, and the like.

Alternatively, the above coupling step can be carried out by firstconverting 4 into an active acid derivative such as succinimide esterand then reacting it with an amine of formula 5. The reaction typicallyrequires 2 to 3 h to complete. The conditions utilized in this reactiondepend on the nature of the active acid derivative. For example, if itis an acid chloride derivative of 4, the reaction is carried out in thepresence of a suitable base (e.g. triethylamine, diisopropylethylamine,pyridine, and the like). Suitable reaction solvents are polar organicsolvents such as acetonitrile, N,N-dimethylformamide, dichloromethane,or any suitable mixtures thereof.

It will be apparent to a person skilled in the art, that compounds ofFormula (I) can also be prepared by first condensing 5 with theN-protected amino acid of formula 2 where R is hydrogen followed byremoval of the amino protecting group and reacting the free aminocompound with a compound of formula 1 as described in Scheme 1 above.Suitable amino acid protecting groups and reaction conditions forputting them on and removing them can be found in Greene, T. W.; andWuts, P. G. M.; Protecting Groups in Organic Synthesis; John Wiley &Sons, Inc. 1999.

Alternatively, a compound of Formula (I) where R¹, R², R³, R⁴ and R^(4′)are as defined in the Summary of the Invention can be prepared asillustrated and described in Scheme 2 below.

Reaction of a compound of formula 7 where R³ is as defined in theSummary of the Invention and PG is a suitable oxygen protecting groupwith a hemiacetal of formula 6 provides an imine compound of formula 8.Treatment of 8 with an organolithium compound of formula R⁴Li where R⁴is as defined in the Summary of the Invention provides compound 9.Removal of the oxygen protecting group, followed by oxidation of theresulting alcohol 10 provides a compound of formula 4 which is thenconverted to a compound of Formula (I) as described in Scheme 1 above.Suitable oxygen protecting groups and reaction conditions for puttingthem on and removing them can be found in Greene, T. W.; and Wuts, P. G.M.; Protecting Groups in Organic Synthesis; John Wiley & Sons, Inc.1999.

Alternatively, a compound of Formula (I) where R¹, R², R³, R⁴, andR^(4′) are as defined in the Summary of the Invention and can beprepared as illustrated and described in Scheme 3 below.

Reaction of a compound of formula 2 where R is alkyl and R³ is asdefined in the Summary of the Invention with a hemiacetal compound offormula 6 provides a 2-(1-hydroxy-2,2,2-trifluoroethylamino)acetatecompound of formula 11. The reaction is carried out in the presence of acatalytic amount of an acid such as p-toluenesulfonic acid and in anaromatic hydrocarbon solvent such as toluene, benzene, and the like.

Treatment of 11 with a compound of formula R⁴H where R⁴ is as defined inthe Summary of the Invention under Friedel-Crafts reaction conditionsprovides a compound of formula 3 which is then converted to a compoundof Formula (I) as described above.

Alternatively, the compound of Formula (I) where R¹, R², R³, and R⁴ areas defined in the Summary of the Invention and R^(4′) is trifluoromethylcan be prepared as illustrated and described in Scheme 4 below.

Reaction of a compound of formula 13 where R⁴ is as defined in Summaryof the Invention with a compound of formula 14 where R′ is hydrogen or acarboxy protecting group and R^(z) is R³ or a precursor group (e.g.,-alkylene-5-trityl or -alkylene-5-alkylene-heteroaryl) to R³ groupprovides a compound of formula 15. The reaction is carried out in asuitable organic solvent, including but not limited to, diethyl ether,tetrahydrofuran, acetonitrile, benzene, toluene, xylene, and the like,or mixtures thereof and optionally in the presence of an organic orinorganic base. Preferably, the organic base is triethylamine, pyridine,N-methylmorpholine, collidine, diisopropylethylamine, and the like.Preferably, the inorganic base is cesium carbonate, sodium carbonate,sodium bicarbonate, and the like. The reaction is optionally carried outin the presence of a drying agent such as molecular sieves. Preferably,the reaction is carried out at room temperature.

Compounds of formula 13 can be prepared by methods well known in theart. For example, a compound of formula 13 where R⁴ is phenyl or4-fluorophenyl can be readily prepared from commercially available2,2,2-trifluoroacetophenone or 2,2,2,4′-tetrafluoroacetophenonerespectively, by reducing the keto group to an alcoholic group bysuitable reducing agent such as sodium borohydride, lithium aluminumhydride, and the like. The solvent used depends on the type of reducingagent. For example, when sodium borohydride is used the reaction iscarried out in an alcoholic organic solvent such as methanol, ethanol,and the like. When lithium aluminum hydride is used the reaction iscarried out in an ethereal solvent such as tetrahydrofuran, and thelike. Reaction of 2,2,2-trifluoro-1-phenylethanol or2,2,2-trifluoro-1-(4-fluorophenyl)ethanol with triflic anhydride ortrifluoromethanesulfonyl chloride provides the desired compound.Optically enriched compound of formula 15 can be obtained by reductionof the corresponding halogenated acetophenone with a suitable reducingagent such as catecholborane or BH₃-DMS complex in the presence of asuitable catalyst such as (S) or (R)-CBS oxazaborolidine catalyst or (S)or (R)-α,α-diphenyl-2-pyrrolidine-methanol in the presence of BBN toprovide chiral alcohol which is then converted to compound 13 asdescribed above. Compounds of formula 14 can be prepared by methods wellknown in the art.

Removal of the carboxy protecting group from a compound of formula 15where R′ is a protecting group provides a compound of formula 16. Theconditions used to remove the carboxy protecting group depend on thenature of the carboxy protecting group. For example, if R′ is alkyl, itis removed under basic hydrolysis reaction conditions utilizing aqueousbase such as aqueous lithium hydroxide, sodium hydroxide, and the likein an alcoholic solvent such as methanol, ethanol, and the like.Additionally, if the R^(z) group in compound 14 is a precursor group toR³ it can be converted to R³ or to another precursor group to R³ (e.g.,converting -alkylene-5-trityl to -alkylene-5-alkylene-heteroaryl, andthe like) prior to proceeding further.

Compound 15 (where R′ is hydrogen) or 16 is then converted to anactivated acid derivative 17 (X is a leaving group) and which uponreaction with an aminoacetonitrile compound of formula 5 provides acompound of Formula (I) when R^(z) is R³ or a precursor compound to (I)when R^(z) is a precursor group to R³. The activated acid derivative canbe prepared and then reacted with compound 5 in a stepwise manner or theacid derivative can be generated in situ in the presence of compound 5.For example, if the activated acid is acid halide it is first preparedby reacting 16 with a halogenating agent such as thionyl chloride,oxalyl, chloride and the like and then reacted with compound 5.Alternatively, the activated acid derivative is generated in situ byreacting compound 16 and 5 in the presence of a suitable coupling agente.g., benzotriazole-1-yloxytrispyrrolidinophosphoniumhexafluorophosphate (PyBOP®),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),1,3-dicyclohexyl-carbodiimide (DCC), an the like, optionally in thepresence of 1-hydroxybenzotriazole (HOBT), and in the presence of a basesuch as N,N-diisopropylethylamine, triethylamine, N-methylmorpholine,and the like. Suitable reaction solvents are inert organic solvents suchas halogenated organic solvents (e.g., methylene chloride, chloroform,and the like), acetonitrile, N,N-dimethylformamide, ethereal solventssuch as tetrahydrofuran, dioxane, and the like. Alternatively, theactivated acid can be reacted with CR¹R²(NH₂)CONH₂ where R¹ and R² areas described in the Summary of the Invention, followed by conversion ofthe —CONH₂ group to the cyano group by methods well known in the art. IfR^(z) is a precursor group to R³, it is converted to R³ group to providea compound of Formula (I) e.g., conversion of-alkylene-5-alkylene-heteroaryl to -alkylene-SO₂-alkylene-heteroarylunder oxidation reaction conditions.

A compound of Formula (I) can be converted to other compounds of Formula(I). For example:

A compound of Formula (I) containing a hydroxy group may be prepared byde-alkylation/benzylation of an alkoxy/benzyloxy substituent; thosecontaining an acid group, by hydrolysis of an ester group; and thosecontaining a cyano, by displacement of a bromine atom on thecorresponding compounds of Formula (I). A compound of Formula (I)containing a halo group such as chloro can be converted to acorresponding compound of Formula (I) containing an methylthio bytreating it with sodium thiomethoxide. The methylthio group can beoxidized to methylsulfonyl using a suitable oxidizing agent such asOXONE®. A compound of Formula (I) containing a cyano group can beconverted to a corresponding carboxy containing compound by hydrolysisof the cyano group. The carboxy group, in turn, can be converted to anester group.

A compound of Formula (I) can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of Formula (I) can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Inorganic and organic acids and bases suitable for the preparationof the pharmaceutically acceptable salts of compounds of Formula (I) areset forth in the definitions section of this application. Alternatively,the salt forms of the compounds of Formula (I) can be prepared usingsalts of the starting materials or intermediates.

The free acid or free base forms of the compounds of Formula (I) can beprepared from the corresponding base addition salt or acid addition saltform. For example, a compound of Formula (I) in an acid addition saltform can be converted to the corresponding free base by treating with asuitable base (e.g., ammonium hydroxide solution, sodium hydroxide, andthe like). A compound of Formula (I) in a base addition salt form can beconverted to the corresponding free acid by treating with a suitableacid (e.g., hydrochloric acid, etc).

The N-oxides of compounds of Formula (I) can be prepared by methodsknown to those of ordinary skill in the art. For example, N-oxides canbe prepared by treating an unoxidized form of the compound of Formula(I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleicacid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, orthe like) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds of Formula (I) can beprepared from the N-oxide of an appropriate starting material.

Compounds of Formula (I) in unoxidized form can be prepared fromN-oxides of compounds of Formula (I) by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) inan suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of Formula (I) can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al.(1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of Formula (I) with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of Formula (I) can be made bymeans known to those of ordinary skill in the art. A detaileddescription of the techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may be conveniently prepared orformed during the process of the invention, as solvates (e.g. hydrates).Hydrates of compounds of the present invention may be convenientlyprepared by recrystallisation from an aqueous/organic solvent mixture,using organic solvents such as dioxin, tetrahydrofuran or methanol.

Compounds of Formula (I) can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomer. While resolution of enantiomers can be carried outusing covalent diasteromeric derivatives of compounds of Formula (I),dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

Preparation of Biological Agents

In practicing this invention several processes for the generation orpurification of biological agents are used. Methods for preparing thebiologics are well known in the art as discussed below.

Monoclonal antibodies are prepared using standard techniques, well knownin the art, such as by the method of Kohler and Milstein, Nature 1975,256:495, or a modification thereof, such as described by Buck et al.1982, In Vitro 18:377. Typically, a mouse or rat is immunized with theMenB PS derivative conjugated to a protein carrier, boosted and thespleen (and optionally several large lymph nodes) removed anddissociated into single cells. If desired, the spleen cells may bescreened (after removal of non-specifically adherent cells) by applyinga cell suspension to a plate or well coated with the antigen. B-cells,expressing membrane-bound immunoglobulin specific for the antigen, willbind to the plate, and will not be rinsed away with the rest of thesuspension. Resulting B-cells, or all dissociated spleen cells, are theninduced to fuse with myeloma cells to form hybridomas. Representativemurine myeloma lines for use in the hybridizations include thoseavailable from the American Type Culture Collection (ATCC).

Chimeric antibodies composed of human and non-human amino acid sequencesmay be formed from the mouse monoclonal antibody molecules to reducetheir immunogenicity in humans (Winter et al. Nature 1991 349:293;Lobuglio et al. Proc. Nat. Acad. Sci. USA 1989 86:4220; Shaw et al. J.Immunol. 1987 138:4534; and Brown et al. Cancer Res. 1987 47:3577;Riechmann et al. Nature 1988 332:323; Verhoeyen et al. Science 1988239:1534; and Jones et al. Nature 1986 321:522; EP Publication No.519,596, published Dec. 23, 1992; and U.K. Patent Publication No. GB2,276,169, published Sep. 21, 1994).

Antibody molecule fragments, e.g., F(ab′).sub.2, FV, and sFv molecules,that are capable of exhibiting immunological binding properties of theparent monoclonal antibody molecule can be produced using knowntechniques. Inbar et al. Proc. Nat. Acad. Sci. USA 1972 69:2659; Hochmanet al. Biochem. 1976 15:2706; Ehrlich et al. Biochem. 1980 19:4091;Huston et al. Proc. Nat. Acad. Sci. USA 1988 85(16):5879; and U.S. Pat.Nos. 5,091,513 and 5,132,405, and U.S. Pat. No. 4,946,778.

In the alternative, a phage-display system can be used to expand themonoclonal antibody molecule populations in vitro. Saiki, et al. Nature1986 324:163; Scharf et al. Science 1986 233:1076; U.S. Pat. Nos.4,683,195 and 4,683,202; Yang et al. J. Mol. Biol. 1995 254:392; Barbas,I I I et al. Methods: Comp. Meth Enzymol. 1995 8:94; Barbas, I I I etal. Proc. Natl. Acad. Sci. USA 1991 88:7978.

The coding sequences for the heavy and light chain portions of the Fabmolecules selected from the phage display library can be isolated orsynthesized, and cloned into any suitable vector or replicon forexpression. Any suitable expression system can be used, including, forexample, bacterial, yeast, insect, amphibian and mammalian systems.Expression systems in bacteria include those described in Chang et al.Nature 1978 275:615, Goeddel et al. Nature 1979 281:544, Goeddel et al.Nucleic Acids Res. 1980 8:4057, European Application No. EP 36,776, U.S.Pat. No. 4,551,433, deBoer et al. Proc. Natl. Acad. Sci. USA 198380:21-25, and Siebenlist et al. Cell 1980 20:269. Expression systems inyeast include those described in Hinnen et al. Proc. Natl. Acad. Sci.USA 1978 75:1929, Ito et al. J. Bacteriol. 1983 153:163, Kurtz et al.Mol. Cell. Biol. 1986 6:142, Kunze et al. J. Basic Microbiol. 198525:141, Gleeson et al. J. Gen. Microbiol. 1986 132:3459, Roggenkamp etal. Mol. Gen. Genet. 1986 202:302, Das et al. J. Bacteriol. 1984158:1165, De Louvencourt et al. J. Bacteriol. 1983 154:737, Van den Berget al. Bio/Technology 1990 8:135, Kunze et al. I Basic Microbiol. 198525:141, Cregg et al. Mol. Cell. Biol. 1985 5:3376, U.S. Pat. Nos.4,837,148 and 4,929,555, Beach et al. Nature 1981 300:706, Davidow etal. Curr. Genet. 1985 10:380, Gaillardin et al. Curr. Genet. 1985 10:49,Ballance et al. Biochem. Biophys. Res. Commun. 1983 112:284-289, Tilburnet al. Gene 1983 26:205-221, Yelton et al. Proc. Natl. Acad. Sci. USA1984 81:1470-1474, Kelly et al. EMBO J. 1985 4:475479; EuropeanApplication No. EP 244,234, and International Publication No. WO91/00357.

Expression of heterologous genes in insects can be accomplished asdescribed in U.S. Pat. No. 4,745,051, European Application Nos. EP127,839 and EP 155,476, Vlak et al. J. Gen. Virol. 1988 69:765-776,Miller et al. Ann. Rev. Microbiol. 1988 42:177, Carbonell et al. Gene1988 73:409, Maeda et al. Nature 1985 315:592-594, Lebacq-Verheyden etal. Mol. Cell. Biol. 1988 8:3129, Smith et al. Proc. Natl. Acad. Sci.USA 1985 82:8404, Miyajima et al. Gene 1987 58:273, and Martin et al.DNA 1988 7:99. Numerous baculoviral strains and variants andcorresponding permissive insect host cells from hosts are described inLuckow et al. Bio/Technology 1988 6:47-55, Miller et al. GENETICENGINEERING, Setlow, J. K. et al. eds., Vol. 8, Plenum Publishing, pp.1986 277-279, and Maeda et al. Nature 1985 315:592-594.

Mammalian expression can be accomplished as described in Dijkema et al.EMBO J. 1985 4:761, Gorman et al. Proc. Natl. Acad. Sci. USA 198279:6777, Boshart et al. Cell 1985 41:521, and U.S. Pat. No. 4,399,216.Other features of mammalian expression can be facilitated as describedin Ham et al. Meth. Enz. 1979 58:44, Barnes et al. Anal. Biochem. 1980102:255, U.S. Pat. Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655 andReissued U.S. Pat. No. RE 30,985, and in International Publication Nos.WO 90/103430, WO 87/00195.

The production of recombinant adenoviral vectors are described in U.S.Pat. No. 6,485,958.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures.

Any of the above-described protein production methods can be used toprovide the biologic that would benefit from the present invention.

Pharmacology and Utility

The compounds of the invention are selective inhibitors of cysteineproteases such as cathepsin S, K, B, and/or F, and in particularcathepsin S, and accordingly are useful for treating diseases in whichcysteine protease activity contributes to the pathology and/orsymptomatology of the disease. For example, the compounds of theinvention are useful in treating autoimmune disorders, including, butnot limited to, juvenile onset diabetes, psoriasis, multiple sclerosis,pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupuserythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis,allergic disorders, including, but not limited to, asthma, allogeneicimmune responses, including, but not limited to, organ transplants ortissue grafts and endometriosis.

Cathepsin S is also implicated in disorders involving excessiveelastolysis, such as chronic obstructive pulmonary disease (e.g.,emphysema), bronchiolitis, excessive airway elastolysis in asthma andbronchitis, pneumonities and cardiovascular disease such as plaquerupture and atheroma. Cathepsin S is implicated in fibril formation and,therefore, inhibitors of cathepsins S are of use in treatment ofsystemic amyloidosis.

The cysteine protease inhibitory activities of the compounds of Formula(I) can be determined by methods known to those of ordinary skill in theart. Suitable in vitro assays for measuring protease activity and theinhibition thereof by test compounds are known. Typically, the assaymeasures protease-induced hydrolysis of a peptide-based substrate.Details of assays for measuring protease inhibitory activity are setforth in Biological Examples 1-5, infra.

Administration and Pharmaceutical Compositions

In general, compounds of Formula (I) will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Forexample, therapeutically effective amounts of a compound of Formula (I)may range from about 10 micrograms per kilogram body weight (μg/kg) perday to about 100 milligram per kilogram body weight (mg/kg) per day,typically from about 100 μm/kg/day to about 10 mg/kg/day. Therefore, atherapeutically effective amount for an 80 kg human patient may rangefrom about 1 mg/day to about 8 g/day, typically from about 1 mg/day toabout 800 mg/day. In general, one of ordinary skill in the art, actingin reliance upon personal knowledge and the disclosure of thisapplication, will be able to ascertain a therapeutically effectiveamount of a compound of Formula (I) for treating a given disease.

The compounds of Formula (I) can be administered as pharmaceuticalcompositions by one of the following routes: oral, systemic (e.g.,transdermal, intranasal or by suppository) or parenteral (e.g.,intramuscular, intravenous or subcutaneous). Compositions can take theform of tablets, pills, capsules, semisolids, powders, sustained releasefoimulations, solutions, suspensions, elixirs, aerosols, or any otherappropriate composition and are comprised of, in general, a compound ofFormula (I) in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the activeingredient. Such excipient may be any solid, liquid, semisolid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk, and the like. Liquid and semisolid excipientsmay be selected from water, ethanol, glycerol, propylene glycol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesameoil, and the like). Preferred liquid carriers, particularly forinjectable solutions, include water, saline, aqueous dextrose andglycols.

The amount of a compound of Formula (I) in the composition may varywidely depending upon the type of formulation, size of a unit dosage,kind of excipients and other factors known to those of skill in the artof pharmaceutical sciences. In general, a composition of a compound ofFormula (I) for treating a given disease will comprise from 0.01% w to10% w, preferably 0.3% w to 1% w, of active ingredient with theremainder being the excipient or excipients. Preferably thepharmaceutical composition is administered in a single unit dosage formfor continuous treatment or in a single unit dosage form ad libitum whenrelief of symptoms is specifically required. Representativepharmaceutical formulations containing a compound of Formula (I) aredescribed in Example 1 below.

EXAMPLES

The present invention is further exemplified, but not limited by, thefollowing examples that illustrate the preparation of compounds ofFormula (I) (Examples) and intermediates (References) according to theinvention.

Reference A Synthesis of trifluoromethanesulfonic acid2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester

Step 1

To a stirred solution of 2,2,2,4′-tetrafluoroacetophenone (10 g, 52.1mmol) in methanol (50 mL) was added NaBH₄ (0.98 g, 26.5 mmol) at 0° C.After stirring at 25° C. for 2 h, the reaction mixture was quenched byadding 1N HCl (100 mL) and then extracted with ethyl ether. The etherextract was washed with brine, dried with MgSO₄, and concentrated togive 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (11.32 g) which was usedin next step without further purification.

Step 2

NaH (640 mg, 16 mmol, 60% in mineral oil) was washed twice with hexane(20 mL) and then suspended in dried diethyl ether (20 mL). A solution of2,2,2-trifluoro-1-(4-fluoro-phenyl)ethanol (1.94 g, 10 mmol) in diethylether (10 mL) was added at 0° C. After stirring for 2 h at roomtemperature, a solution of trifluoromethanesulfonyl chloride (1.68 g, 10mmol) in diethyl ether (10 mL) was added. After 2 h, the reactionmixture was quenched by adding a solution of sat NaHCO₃ and the productwas extracted with diethyl ether. The extracts were washed with brineand dried, and the solvent was removed to yield trifluoromethanesulfonicacid 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester (3.3 g).

Reference B Synthesis of 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethanol

To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-methyl CBSoxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added freshly distilledcatecholborane (1.66 mL, 15.62 mmol). The reaction mixture wasmaintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane)was added and the reaction mixture was allowed to warm to roomtemperature. The reaction mixture was diluted with ethyl acetate andwashed with a saturated brine solution. The organic layer was dried overmagnesium sulfate, filtered and concentrated to provide a solid. Thesolid was suspended in hexanes and filtered off. The hexanes filtratecontaining the desired product was concentrated and the residuesubjected to flash chromatography (hexanes:ethylacetate 1:10) to providethe title compound as a colorless oil (2.2 g, 87% yield). The ratio ofenantiomers was determined to be 95:5 by chiral HPLC (Chiralcel ODcolumn, 95 hexanes: 5 isopropanol mobile phase. Ret. time of the majorproduct was 6.757 min. Ret. Time for the minor isomer was 8.274 min.).

2,2,2-Trifluoro-1(S)-(4-fluorophenyl)ethanol can be prepared by usingR-methyl CBS oxazaborolidine.

Reference C Synthesis of 1-aminocyclopropanecarbonitrile hydrochloride

Step 1

A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) andaminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) indichloromethane (1000 mL) was stirred in a 2 L Erlenmeyer flask undernitrogen at room temperature for 5 days. The reaction mixture wasfiltered to remove the precipitated ammonium chloride and the filtratewas evaporated to dryness in vacuo. The resulting residue was dissolvedin ether (400 mL) washed with water (200 mL) and brine. After dryingover magnesium sulfate the solution was evaporated to give(benzhydrylideneamino)-acetonitrile (47.89 g).

Step 2

A solution of sodium hydroxide (91 g, 2.275 mol) in water (91 mL) in a 2L flask was cooled on ice under nitrogen and then treated with benzyltriethyl ammonium chloride (2.0 g, 0.0088 mol, Aldrich) and(benzhydrylideneamino)acetonitrile (47.89 g) in toluene (100 mL).

1,2-Dibromoethane (23 mL, 122.4 mmol, Aldrich) was then added dropwiseover 25 min, to the reaction mixture with mechanical stirring andcooling to maintain the internal temperature near +10° C. The reactionmixture was then stirred vigorously for 24 h at room temperature andthen poured into ice water and extracted with toluene. The combinedextracts were washed with brine and then treated with MgSO₄ and Norite.After filtering, toluene was removed by rotary evaporation to give anoil (67 g). The residue was dissolved in boiling hexane (400 mL),treated with Norite and filtered hot and allowed to cool. A dark oilseparated which was removed by pipette (˜2 mL). Scratching inducedcrystallization in the remaining solution which was cooled on ice for 2h. Light yellow crystals were collected by filtration and washed withcold hexane to give 1-(benzhydrylideneamino)cyclopropanecarbonitrile(30.56 g).

Step 3

A mixture of 1-(benzhydrylideneamino)cyclopropanecarbonitrile (30.56 g,0.124 mol) in concentrated HCl (12 mL) in water (100 mL) and ether (100mL) was stirred at room temperature for 15 h. The ether layer wasdiscarded and the aqueous layer was washed with ether. The aqueous layerwas then freeze dried to give the title compound as a tan powder (13.51g). This compound is also commercially available.

Reference D Synthesis of2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionicacid

To a slurry of S-trityl-L-cysteine (4.86 g, 13.37 mmol) indichloromethane (97 mL, 20 mL/g AA) at room temperature was addeddiisopropylethylamine (9.32 mL, 53.48 mmol) followed by a solution oftrifluoromethanesulfonic acid 2,2,2-trifluoro-1(RS)-phenylethyl ester(5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) in dichloromethane(15 mL) via syringe all at once. After 19 h, the reaction mixture wasconcentrated on the rotovap to give an oil. Diethyl ether was added andthe solution was washed with 1N HCl and brine. The organic layer wasdried over MgSO₄, filtered, and concentrated. Flash chromatography ofthe residue with 2 hexanes/1 ethyl acetate/0.25% acetic acid as theeluent provided2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionicacid (6 g) (major diastereomer (R,S), 90 de) as an oil/foam.

Reference E Synthesis of2(R)-amino-3-cyclopropylmethylsulfanylpropan-1-ol

Step 1

An ice water bath cooled solution of L-cysteine in 1N sodium hydroxide(740 mL) and dioxane (740 mL) was treated with bromomethylcyclopropane(50 g, 370 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred for 16 h. Dioxane was removed under reducedpressure and the resulting aqueous solution was adjusted to pH 6 with 6NHCl and placed in a refrigerator for 20 h. The product was collected byvacuum filtration, washed with hexanes and lyophilized to give2(R)-amino-3-cyclopropylmethylsulfanylpropionic acid (57.28 g) as awhite solid.

Step 2

To an ice water cooled solution of lithium aluminum hydride (200 mL of1.0 M) was added solid 2(R)-amino-3-cyclopropylmethylsulfanylpropionicacid. The addition was done by tapping in portions through a funnel insuch a manner as to control hydrogen gas evolution. The ice bath wasremoved, and the reaction mixture was heated at reflux for 16 h. Thereaction mixture was removed from heat and cooled in an ice water bath.Diethyl ether (110 mL) was added, followed by dropwise addition of water(5 mL), 15% aqueous sodium hydroxide (5 mL), and water (15 mL). Afterstirring in the ice water bath for 1.5 h, the reaction mixture wasfiltered. The filtrate was dried over anhydrous sodium sulfate, andconcentrated to give 2(R)-amino-3-cyclopropylmethylsulfanyl-propan-1-ol(14.9 g).

Example 1 Synthesis ofN-(1-cyanocyclopropyl)-3-pyridin-3-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;Compound 2

Step 1

To a solution of2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-trityl-sulfanylpropionicacid (539 mg, 1 mmol, 90% de), prepared as described above, in CH₂Cl₂was added trifluoroacetic acid (0.4 mL, 4 mmol) and triethylsilane (0.4mL, 2 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture waswarmed up to room temperature and stirred for 2 h. The solvent wasremoved under reduced pressure and the residue was dissolved in 1N NaOH(12 mL). The aqueous layer was washed with hexane and to the basicsolution was added dioxane (12 mL), P(CH₂CH₂COOH)₃.HCl (28 mg, 0.1 mmol)and 3-chloromethyl-pyridine (196 mg, 1.2 mmol) and the reaction mixturewas stirred at room temperatute 2h. The dioxane was removed under educedpressure and residue was acidified with 6N HCl to pH 5. The product wasextracted with ethyl acetate and after drying the organic extracts withMgSO₄, the solvent was removed to give2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethyl-amino]-3-(pyridin-3-ylmethylsulfanyl)propionicacid which was used in the next step without further purification.

Step 2

2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(pyridin-3-ylmethylsulfanyl)-propionicacid was dissolved in DMF (5 mL) and 1-aminocyclopropanecarbonitrile(142 mg, 1.2 mmol), HATU (456 mg, 1.2 mmol) and NMM (0.44 mL, 4 mmol)were added. After stirring for 2 h at rt, saturated NH₄Cl and ethylacetate were added and stirring was continued for 20 min. The aqueouslayer was extracted with ethyl acetate. The combined organic layers weredried with MgSO₄ and the solvent was removed under the reduced pressureto give N-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(pyridin-3-ylmethylsulfanyl)propionamideas an oil. The crude was used in the next step without furtherpurification.

Step 3

N-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(pyridin-3-ylmethylsulfanyl)propionamidewas dissolved in MeOH (3 mL) and OXONE® (460 mg, 1.5 mmol) in H₂O (3 mL)was added. After stirring at rt for 2 h, the solvent was removed and theresidue was extracted with ethyl acetate. The organic layer was driedwith MgSO₄ and the solvent was removed under reduced pressure. The titlecompound was purified by Prep-HPLC.

Example 2 Synthesis ofN-(1-cyanocyclopropyl)-3-(difluoropyridin-2-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino]propionamideCompound 23

Step 1

To a solution of (Boc-Cys-OH)₂ (20 g, 45.4 mmol) and P(CH₂CH₂COOH)₃.HCl(15.61 g, 54.47 mmol) in DMF (162 mL) was added 5N KOH (109 mL) slowlyover 20 min. After stirring overnight, 2-picolylchloride hydrochloride(22.34 g, 136.2 mmol) was added in one portion and the reaction mixturewas stirred at room temperature for 2.5h. The pH of the solution wasadjusted to 3 with 10N HCl and the product was extracted with methylenechloride. The combined organic extract was washed with sat. NaHCO₃,dried over MgSO₄, filtered and concentrated to give2(R)—N-tert-butoxycarbonylamino-3-(pyridin-2-ylmethylsulfanyl)propionicacid which was crystallized from methylene chloride and hexane mixtureto give pure product (13.70 g) as a white solid.

Step 2

2(R)—N-tert-Butoxycarbonylamino-3-(pyridin-2-ylmethylsulfanyl)propionicacid (3.12 g, 10 mmol) was dissolved in mixture of methanol (10 mL) andbenzene (10 mL). Trimethylsilyl-diazomethane (10 mL, 2.0M solution inhexane, 20 mM) was added slowly. After 1 h, the solvent was removed togive methyl2(R)—N-tert-butoxycarbonylamino-3-(pyridin-2-ylmethyl-sulfanyl)-propionateas a yellow oil.

Step 3

Methyl2(R)—N-tert-butoxycarbonylamino-3-(pyridin-2-ylmethylsulfanyl)-propionatewas dissolved in dioxane and 3 equiv. of 4M HCl in dioxane was added.After stirring at room temperature for 3 h, the solvent was removedunder reduced pressure to give methyl2(R)-amino-3-(pyridin-2-ylmethylsulfanyl)propionate hydrochloride as ahygroscopic solid.

Step 4

To a mixture of methyl2(R)-amino-3-(pyridin-2-ylmethylsulfanyl)propionate hydrochloride (1.31g, 5 mmol), 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (0.875 g), DIPEA(2.39 g, 18.5 mmol), in dichloromethane (20 mL) was added titaniumtetrachloride (4.65 mmol) dropwise over 5 min. After stirring for 3 h atambient temperature, additional titanium tetrachloride (0.3 mmol) wasadded. After an additional hour of stirring, NaCNBH₄ (0.973 g, 15.5mmol) was added in methanol (10 mL). After 1 h, the reaction mixture wasdiluted with ethyl acetate (200 mL) and poured onto magnesium sulfate.After filtration and concentration, the residue was purified by flashchromatography to afford methyl3-(pyridin-2-yl-methylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]-propionate(640 mg, 1.59 mmol).

Step 5

To a solution of methyl3-(pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionate(0.64 g, 1.59 mmol) in methanol (9 mL) was added 1N sodium hydroxide(4.77 mL). The resulting solution was stirred for 2 h at ambienttemperature and then methanol was removed in vacuo. The residue wasportioned between water and ethyl acetate. The aqueous layer wasextracted twice more with ethyl acetate and the combined organic layerswere dried over magnesium sulfate. Removal of the solvents provided3-(pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionic acid (0.410 g, 1.06 mmol) as awhite solid which was a mixture of diastereomers.

3-(Pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]-propionicacid was converted to ofN-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionamide by proceeding as describedin Example 1, Step 2 above.N-(1-Cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide(95 mg) was obtained from the diasteriomeric mixture by flashchromatography and was converted toN-(1-cyano-cyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethyl-amino)propionamidecompound (50 mg) by proceeding as described in Example 1, Step 3 above.

Step 6

ToN-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide(0.200 g, 0.412 mmol) in dichloromethane (5 mL) was added DIPEA (0.058g, 4.53 mmol) and the slight suspension cooled in an ice-water bath.Boc-anhydride (0.099 mg, 0.453 mmol) was added in one portion and theresulting opaque solution was allowed to warm to ambient temperatureovernight. The reaction was diluted to 100 mL with EtOAc and the organicphase extracted once with 10 mL 0.1 N HCl, sodium bicarbonate, and brineand dried over MgSO₄. Removal of solvent afforded[1(R)-(1-cyanocyclopropyl-carbamoyl)-2-(pyridin-2-ylmethanesulfonyl)ethyl]-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethyl]carbamicacid tert-butyl ester (0.200 g) as a white solid, which was used withoutfurther purification.

Step 7

To a 0.5M solution of potassium bis(trimethylsilyl)amide (1.02 mmol) intoluene, cooled to −78° C., was added[1(R)-(1-cyanocyclopropylcarbamoyl)-2-(pyridin-2-ylmethanesulfonyl)-ethyl]-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethyl]carbamicacid tert-butyl ester (0.2 g, 0.34 mmol) in THF (2 mL) and the brownsolution was stirred for 40 min at −78° C. MnBr₂ was added as a solid,in one portion, resulting in a brown suspension. After stirring for 30min, (PhSO₂)₂NF (0.304 g, 0.964 mmol) was added as a solid and thereaction mixture was stirred at −78° C. for 30 min, then allowed to warmto ambient temperature overnight. After partitioning between 0.5 N HCland EtOAc the organic phase was extracted with bicarbonate, brine, anddried over MgSO₄. The crude residue was purified via flashchromatography with EtOAc/hexanes (0 to 40% EtOAc gradient) affordingthe title compound. MS: 519.2, (M−1) 543.1 (M+23). Also,N-(1-cyanocyclopropyl)-3-(fluoropyridin-2-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamidewas isolated as a diastereomeric mixture.

Example 3 Synthesis ofN-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2-difluoro-1(5)-4-fluorophenylethylamino)propionamide;Compound 48

Step 1

A solution of 2(R)-amino-3-cyclopropylmethylsulfanylpropan-1ol (4.9 g,30.4 mmol), difluoroacetaldehyde ethyl hemiacetal (4.6 g, 36.5 mmol),and PPTS (415 mg) in toluene (100 mL) was heated at reflux with DeanStark trapping of water for 4 h. After cooling to ambient temperature,the solution was filtered through a pad of silica gel and concentratedto an oil. The oil was further purified via silica gel chromatographywith 1:1(v/v) hexanes: diethyl ether as the elution solvent.Concentration of the appropriate fractions yielded a diastereomericmixture of 4-cyclopropylmethylsulfanylmethyl-2-difluoromethyloxazolidine(4.2 g) as a clear oil.

Part A:

A solution of4-cyclopropylmethylsulfanylmethyl-2-difluoromethyloxazolidine (2.08 g,9.3 mmol) in anhydrous THF (25 mL) was cooled in an ice/water bath andtreated with chlorotrimethylsilane (1.2 g, 1.4 mL) and lithiumbis(trimethylsilyl)amide (11.2 mL of a 1.0 M solution intetrahydrofuran). The reaction mixture was allowed to stir under icebath cooling for 30 min and then slowly heated to 60° C. for 1 h toensure complete equilibration to the E imine isomer. The reactionmixture containing(2-cyclopropylmethylsulfanyl-1-trimethylsilanyloxy-methylethyl)-(2,2-difluoroethylidene)aminewas allowed to cool to room temperature.

Part B:

A solution of 4-fluorobromobenzene (4.9 g, 27.9 mmol) in anhydroustetrahydrofuran (55 mL) was cooled to −78° C., treated withn-butyllithium (11.15 mL of 2.5 M solution in hexanes) and allowed tostir for 15 min. The solution from Part A was transferred by syringe tothis reaction mixture at −78° C. over 10 min. Stirring at −78° C. for 2h was followed by addition of aq 2.5 N HCl (10 mL), then the reactionmixture was allowed to warm to room temperature and stirred at roomtemperature for 30 min. Potassium hydroxide (9 mL of 25% solution inwater) was added and the reaction mixture was extract 2 times with 100mL portions of diethyl ether. The combined organic layers were driedover MgSO₄, concentrated, and chromatographed using 20% ethyl acetate:80% hexanes (v/v) as the elution solvent. Concentration of theappropriate fractions yielded3-cycloproplymethylsulfanyl-2(R)-[2,2-difluoro-1(S)-(4-fluorophenyl)-ethylamino]propan-1-ol(1.45 g) as a clear oil.

Step 3

A stock solution of H₅IO₆/CrO₃ was prepared as described in Tet. Lett.1998 39(30) pp. 5323-5326. This was done by dissolving H₅IO₆ (11.4 g, 50mmol) and CrO₃ (56 mg, 2.4 mol %) in anhydrous acetonitrile (115 mL) andstirred overnight. The next morning 855 μL of water was added to thestock solution and stirred for an additional 10 min. H₅IO₆/CrO₃ (53 mL)of the stock solution was chilled to 0° with stirring, and a solution of3-cycloproplymethylsulfanyl-2(R)-[2,2-difluoro-1(5)-(4-fluorophenyl)ethylamino]propan-1-ol(1.45 g) in acetonitrile (25 mL) was added dropwise so as to maintainthe reaction temperature at 0° C. After 4 h, isopropanol (50 mL) wasadded. The reaction mixture was allowed to warm to room temperature andthen was concentrated. The resulting solids were partitioned betweenethyl acetate and saturated aqueous KH₂PO₄. The aqueous layer was driedover anhydrous MgSO₄. Removal of solvent gave3-cyclopropylmethylsulfonyl-2(R)-[2,2,-difluoro-1(S)-(4-fluoro-phenyl)ethylamino]-propionicacid (0.95 g).

Step 4

To a solution of3-cyclopropylmethylsulfonyl-2(R)-[2,2,-difluoro-1(S)-(4-fluorophenyl)-ethylamino]propionicacid (0.95 g), 1-aminocyclopropanecarbonitrile HCl salt (400 mg) in DMF(5 mL) at room temperature was added HATU (1.28 g), followed bydiisopropylethylamine (1.68 g/2.26 mL). After being stirred at roomtemperature for 4 hours, the reaction mixture was concentrated underreduced pressure and then partitioned between ethyl acetate and brine.The combined organic extracts were dried over anhydrous MgSO₄ andconcentrated under reduced pressure, and the residue was purified byrecrystallization from 2-propanol to yieldN-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2-[2,2-difluoro-1-(4-fluorophenyl)ethylamino]-propionamideas colorless crystals (250 mg).

¹H NMR sample acquired in d₆-dimethylsulfoxide is referenced to residualCD₃SOCD₂H at 2.49 ppm. ¹H NMR (400 MHz): δ 8.97 (s, 1H), 7.4-7.35 (m,2H), 7.21-7.16 (m, 2H), 6.09 (dt, 1H), 3.98 (m, 1H), 3.53 (m, 1H), 3.40(m, 1H), 3.26-3.20 (m, 2H), 3.17-3.11 (m, 2H), 1.38 (m, 2H), 1.08 (m,1H), 0.99 (m, 1H), 0.80 (m, 1H), 0.6 (m, 2H), 0.38 (m, 2H)

¹³C NMR Sample acquired in d₆-dimethylsulfoxide is referenced toresidual ¹³CD₃SOCD₃ at 39.5 ppm. ¹³C NMR (125 MHz): δ 172.16, 163.04,161.09, 132.12, 130.66, 130.59, 120.37, 118.24, 116.31, 115.28, 115.11,114.37, 62.11, 61.94, 61.76, 58.58, 55.12, 54.38, 19.53, 15.49, 15.45,3.95, 3.82, 3.78. Exact Mass for C₁₉H₂₂F₃N₃O₃S=429.1. ElectrosprayHPLC/MS M+H=430.1, M−H=428.2

Example 4 Synthesis ofN-(1-cyanocyclopropyl)-3-(4-trifluoromethylpyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamideCompound 1

Step 1

4-Trifluoromethylnicotinic acid (2 g, 10.4 mmol) was dissolved in THFand BH₃-THF 1.0M complex (50 mL, 50 mmol) was added at room temperatureunder N₂. The reaction mixture was stirred at room temperatureovernight. 6N HCl was added slowly to quench the reaction. Solvent wasremoved under reduced pressure and the aqueous layer was adjusted to pH5 and extracted with ethyl acetate. The combined organic layers weredried with MgSO₄, filtered and concentrated under the reduced pressure.The crude (4-trifluoromethylpyridin-3-yl)methanol was dissolved inCH₂Cl₂ and SOCl₂ (2.2 mL, 30 mmol) was added at room temperature. Thereaction mixture was stirred at room temperature overnight. The solventwas removed under the reduced pressure and the crude3-chloromethyl-4-trifluoromethylpyridine was used without furtherpurification.

Step 2

Catecholborane (19.4 mL, 182 mmol) in dichloromethane 15 mL) was addedto a dichloromethane solution of S-methyl CBS oxazaborolidine (13 mL, 13mmol) and 2,2,2,4′-tetrafluoroacetopheone (18.2 mL, 130.13 mmol)dropwise at −78° C. in 30 min and stirred at −78° C. overnight. Thereaction mixture was quenched by addition of 4N HCl in dioxane (13 mL)at −78° C., warmed up to room temperature and the solvent was removedunder reduced pressure. 10% NaHSO₃ solution (200 mL) was added and theaqueous layer was extracted with hexane. The organic layer was washedwith water and dried with MgSO₄. The solvent was removed under reducedpressure to give 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (20 g) ascolorless oil (90% d.e.).

Step 3

NaH (11.87 g, 296.7 mmol) was added to Et₂O (700 mL) at 0° C. under N₂and a solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (44.3 g,228.2 mmol) in ether was added at 0° C. under N₂. The reaction mixturewas stirred 10 min at 0° C. then 1 h at room temperature.Trifluoromethanesulfonyl chloride (50 g, 296.7 mmol) in Et₂O was addedat 0° C. under N₂ and the reaction mixture was stirred 10 min at 0° C.and then 3 h at room temperature. The solvent was removed under thereduced pressure and H₂O (100 mL) was added slowly. The aqueous layerwas extracted by hexane and the combined organic layer was dried withMgSO₄. The solvent was removed under the reduced pressure to givetrifluoromethanesulfonic acid 2,2,2-trifluoro-1-(4-fluorophenyl)ethylester (70 g, 90% d.e) as colorless oil.

Step 4

2-Amino-3-tritylsulfanylpropionic acid (78 g, 214.6 mmol) was dissolvedin CH₂Cl₂, DIPEA (112 mL, 643.8 mmol) was added and the reaction mixturewas stirred for 10 min at room temperature. Trifluoromethanesulfonicacid 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester (70 g, 214.6 mmol) inCH₂Cl₂ was added and the reaction mixture was stirred at roomtemperature overnight. Solvent was removed under reduced pressure, theresidue was dissolved in Et₂O and the solution was washed with 1N HCl,brine, and dried with MgSO₄. Solvent was removed to give a mixture of2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionicacid and2(R)-[2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionicacid (90 g, 90% de) as yellow solid.

Step 5

A mixture of 2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionicacid and2(R)-[2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionicacid (5.4 g, 10 mmol) was dissolved in CH₂Cl₂, TFA (3.1 mL, 40 mmol) andEt₃SiH (3.2 mL, 20 mmol) were added at 0° C. under N₂. The reactionmixture was warmed up to room temperature and stirred for 2 h. Solventwas removed under reduced pressure and the residue was dissolved in 120mL of 1N NaOH. The aqueous layer was washed with hexane and used in thenext step without further purification. To the aqueous solution wasadded dioxane (120 mL), 3-chloromethyl-4-trifluoromethylpyridine (1.95g, 10 mmol), and tris(2-carboxyethyl)phosphine hydrochloride (280 mg, 1mmol). The reaction mixture was stirred at room temperature overnight.Dioxane was removed under the reduced pressure. The aqueous solution wasadjusted to pH 3 and was extracted with ethyl acetate. The combinedorganic layer was dried with MgSO₄ and removed under the reducedpressure. The crude product2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(4-trifluoromethylpyridin-3-ylmethylsulfanyl)-propionicacid containing minor amounts of other diasteromer was used in the nextstep without further purification.

Step 6

2(R)-[2,2,2-Trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(4-trifluoromethylpyridin-3-ylmethylsulfanyl)-propionicacid, 1-aminocyclopropanecarbonitrile hydrochloride (1.18 g, 10 mmol),HATU (4.56 g, 12 mmol), and NMM (4.4 mL, 40 mmol) were added to DMF andthe reaction mixture stirred at room temperature for 2 h. Sat. NH₄Cl (10mL) and ethyl acetate (10 mL) were added and stirring was continued for20 min at room temperature. The aqueous layer was extracted with ethylacetate. The combined organic layer was washed with brine and dried overMgSO₄. Solvent was removed under reduced pressure and crude productN-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfanyl)propionamidewas used in the next step without further purification.

Step 7

N-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(4-trifluoromethyl-pyridin-3-ylmethylsulfanyl)-propionamidewas dissolved in CH₃OH (10 mL) and an aqueous solution of Oxone® (3 g in10 mL H₂O, 10 mmol) was added. The reaction mixture was stirred at roomtemperature 3 h. Solvent was removed under the reduced pressure. Theaqueous layer was extracted with ethyl acetate. The organic layer waswashed with brine and dried with MgSO₄. The solvent was removed underthe reduced pressure and the crude product was purified by prep-HPLC toisolate the title compound from the diastereomeric mixture.

¹H-NMR (DMSO-d₆): δ 0.83 (m, 1H), 1.07 (m, 1H), 1.39 (m, 2H), 3.74 (m,2H), 3.83 (b, 1H), 4.43 (m, 1H), 4.98 (q, 2H), 7.27 (t, 2H), 7.49 (t,2H), 7.87 (d, 1H), 8.86 (s, 1H), 8.89 (d, 1H), 9.18 (s, 1H). LC-MS:553(M+1), 551, (M−1), 575(M+23).

The following compounds were prepared by the procedure described inExample 4 above using appropriated starting materials.

-   N-(1.-cyano cyclopropyl)-3-pyridin-3-ylmethanesulfonyl-2    (R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide.    (compound 2), LC-MS: 485(M+1), 507(M+23), 483(M−1).-   N-(1-cyanocyclopropyl)-3-(pyridazin-3-ylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(5)-(4-fluorophenyl)ethylamino]propionamide.    (compound 3), MS (486.2 M+1, 483.9 M−1).

N-(1-cyanocyclopropyl)-3-(2-trifluoromethylfuran-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide,Compound 4, ¹H-NMR: (CDCl₃): 7.47 (1H, s, NH), 7.33-7.29 (2H, m), 7.24(1H, s), 7.07-7.02 (2H, m), 6.79-6.77 (1H, m), 6.60-6.55 (1H, d),4.59-4.4 (2H, ab,), 4.25-4.23 (1H, m), 3.64-3.55 (1H, m), 3.53-3.48 (1H,dd), 3.27-3.21 (1H, dd), 3-2.9 (1H, m), 1.5-1.4 (2H, m), 1.13-1.07 (2H,m).

LC-MS: 540.2 (M−1), 542.3 (M+1), 564.1 (M+Na).

N-(1-cyanocyclopropyl)-3-(2-methylthiazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide,Compound 6, ¹H-NMR: (CDCl₃): 7.41 (1H, s, NH), 7.31-7.27 (2H, m),7.06-7.01 (2H, m), 4.6-4.3 (2H, dd), 4.3-4.23 (1H, m), 3.7-3.64 (1H, m),3.63-3.55 (1H, dd), 3.38-3.3 (1H, aa), 3.2-3.1 (1H, m), 2.65 (3H, s),1.55-1.45 (2H, m), 1.23-1.1 (2H, m). LC-MS: 503(M−1), 504.8 (M+1), 526.9(M+Na).

-   N-(1-cyanocyclopropyl)-3-pyridin-4-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide.    (compound 7), LC-MS: 485(M+1), 483(M−1).-   N-(1-cyanocyclopropyl)-3-(pyrimidin-4-ylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.    (compound 8), MS (486.2 M+1, 484.0 M-1).-   N-(1-cyanocyclopropyl)-3-[2-(1-oxopyrrol-1-ylmethanesulfonyl]-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide.    (compound 9), LC-MS: 501.3 (M−1), 503.0 (M+1), 525.2 (M+Na).-   N-(1-cyanocyclopropyl)-3-pyridin-3-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenylethylamino)propionamide.    (compound 10), LC-MS: 485(M+1), 507(M+23), 483(M−1).

N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(S)-(3-fluorophenyl)ethylamino]propionamide(compound 11) was prepared by replacing 2,2,2,4′-tetrafluoroacetophenonewith commercial 2,2,2,3′-tetrafluoroacetophenone and following theprocedures of Reference B, Reference A, step 2, and Example 4 above, byreplacing trifluoromethanesulfonic acid2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester withtrifluoromethanesulfonic acid 2,2,2-trifluoro-1-(3-fluorophenyl)-ethylester and 3-chloromethyl-4-trifluoromethylpyridine withcyclopropylmethylbromide. MW=447.45; MS (+1)=448.0; MS (−1)=446.2; MS(+Na)=470.0.

-   N-(1-cyanocyclopropyl)-3-(3,3,3-trifluoropropane-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide.    (compound 12), LC-MS: 490(M+1), 512(M+23), 488(M−1).-   N-(1-cyanocyclopropyl)-3-(4-1H-[1.2.4]triazol-1-ylphenylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.    (compound 14), MS (551.2 M+1, 549.4 M−1).-   N-(1-cyanocyclopropyl)-3-[2-(2-oxo-2,3-dihydrobenzimidazol-1-yl)ethanesulfonyl]-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide.    (compound 15), LC-MS: 554(M+1), 576(M+23), 552(M−1).-   N-(1-cyanocyclopropyl)-3-(5-oxo-pyrrolidin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylaminopropionamide.    (compound 16), LC-MS: 491(M+1), 513(M+23), 489(M−1).-   N-(1-cyanocyclopropyl)-3-(2-fluoropyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylaminopropionamide.    (compound 17), LC-MS: 503(M+1), 525(M+23), 501(M−1).

N-(1-cyanocyclopropyl)-3-(quinolin-2-ylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.(compound 25), MS (535.2 M+1, 533.2 M-1).

-   N-(1-cyanocyclopropyl)-3-(2,6-difluorophenylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.    (compound 31), MS (520.2 M+1, 518.1 M−1).-   N-(1-cyanocyclopropyl)-3-(2,4-difluorophenylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.    (compound 32), MS (520.6 M+1, 518.2 M−1).-   N-(1-cyanocyclopropyl)-3-(quinolin-3-ylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.    (compound 33), MS (535.1 M+1, 533.3M−1).-   N-(1-cyanocyclopropyl)-3-(4,4,4-trifluorobutane-1-sulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.    (compound 34) MW=503.44; MS (+1)=504.1; MS (−1)=502.1; MS    (+Na)=526.2. Prepared as described above but replacing    3-chloromethyl-4-trifluoromethylpyridine with commercial    4,4,4-trifluoro-1-bromobutane.

N-(1-cyanocyclopropyl)-3-(2-pyridin-2-ylethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide.(compound 39), LC-MS: 499(M+1), 521(M+23), 497(M−1).

-   N-(1-cyanocyclopropyl)-3-(2-pyridin-3-ylethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide.    (compound 41), LC-MS: 499(M+1), 521(M+23), 497(M−1).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(RS)-2-chloropyridin-5-ylethylamino)propionamide.    (compound 49), LC-MS: 463.2 (M−1), 465.2 (M+1), 487.2 (M+Na).-   N-(1-cyanocyclopropyl)-3-(quinoxalin-2-ylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.    (compound 55), MS (536.2 M+1, 534.4 M−1).-   N-(1-cyanocyclopropyl)-3-(ethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethyl-amino)propionamide.    (compound 62), LC/MS data: M⁺=421.9; M−=420.1.-   N-(1-cyanocyclopropyl)-3-(methanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide.    (compound 68), LC/MS data: M⁺=408.1; M−=406.2.-   N-(1-cyanocyclopropyl)-3-(propane-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethyl-amino)propionamide    (compound 69), LC/MS data M⁺=435.8; M−=434.3.-   N-(1-cyanocyclopropyl)-3-(1H-indol-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;    (compound 70), LC-MS: 523(M+1), 545(M+23), 521(M−1).-   N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,4-difluorophenylethylamino)propionamide;    (compound 73), LC-MS: 503(M+1), 525(M+23), 501(M−1).-   N-(1-cyanocyclopropyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,4-difluorophenylethylamino)propionamide;    (compound 74), LC-MS: 503(M+1), 525(M+23), 501(M−1).-   N-(1-cyanocyclopropyl)-3-[2-(1H-indol-3-yl)ethanesulfonyl]-2-(R)-[2,2,2-trifluoro-1(5)-(4-fluorophenyeethylamino]propionamide.    (compound 75), MS (537.4 M+1, 535.2 M−1).

The heteroarylmethyl halide was either commercially available orprepared as follows:

Synthesis of 5-chloromethylpyrimidine.

5-Methylpyrimidine (3.0 g, 31.9 mmol), N-chlorosuccinamide (5.23 g, 39.2mmol), and benzoyl peroxide (0.077 g, 0.319 mmol) were combined incarbon tetrachloride (100 mL). The suspension was heated for 7 h atreflux. The reaction was cooled, filtered, concentrated and finallypurified via flash chromatography with ethyl acetate/hexanes as eluent.

N-(1-cyanocyclopropyl)-3-(tetrahydro-pyran-4-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluoro-phenyl)-ethylamino]-propionamide.(compound 76), MW=491.51; MS (+1)=492.3; MS (−1)=490.1; MS (+Na)=514.3.

Prepared as described above by replacing3-chloromethyl-4-trifluoromethylpyridine with4-iodomethyltetrahydropyran prepared as described below.

A solution of (tetrahydropyran-4-yl)methanol (0.5 g), triethylamine (1.2mL) and dichloromethane (15 mL) was cooled to −40° C. and treated withmethanesulfonylchloride (333 uL). The reaction mixture was allowed tostir at −40° C. to −20° C. for 2. It was then diluted with 25 mLdichloromethane, washed with water, dried over anhydrous magnesiumsulfate, filtered and concentrated. Acetone (40 mL) and sodium iodide(1.3 g) were added and the reaction mixture was heated at reflux for 16h. The reaction mixture was diluted with dichloromethane and filtered.The filtrate was concentrated to provide 4-iodomethyltetrahydro-pyranwhich was used without further purification.

-   N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1-(3-hydroxy-6-methyl-pyridin-2-yl)-ethylamino]-propionamide.    (compound 85)

MW=460.48; MS (+1)=461.1, MS (−1)=459.0, MS (+Na)=483.1 was prepared byreplacing trifluoromethanesulfonic acid2,2,2-trifluoro-1-(RS)-phenylethyl ester with trifluoro-methanesulfonicacid 2,2,2-trifluoro-1-(3-hydroxy-6-methyl-pyridin-2-yl)-ethyl esterprepared as described below.

6-Methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyridin-3-ol was preparedby a modification of a procedure detailed in J. Heterocyclic Chem., 38,25 (2001), p 25 by replacing traditional heating with microwave heatingas follows.

Step 1

A mixture of commercially available 6-methylpyridin-3-ol (500 mg),trifluoroacetaldehyde methylhemiacetal (715 mg) and potassium carbonate(69 mg) was heated in a microwave reactor at 180° C. for 3 min. Thereaction mixture was partitioned between ethyl acetate and water. Theaqueous layer was extracted with ethyl acetate. The combined organicswere dried over anhydrous sodium sulfate, filtered, and concentrated.The crude product was purified by silica gel chromatography using 1:1hexane:ethyl acetate and recrystallized from ethyl acetate and hexane togive 627 mg of 6-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-ol.

Step 2

-   6-Methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-ol was    converted to trifluoro-methanesulfonic acid    2,2,2-trifluoro-1-(3-hydroxy-6-methyl-pyridin-2-yl)-ethyl ester by    the method described in step 2 of reference A.-   N-(1-cyanocyclopropyl)-3-(2-tert-butyl-[1.3.4]-thiadiazol-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide    (compound 86), LC-MS: 546.1 (M−1), 548.1 (M+1), 569.8 (M+Na).-   N-(1-cyanocyclopropyl)-3-(2,4,6-trifluorophenylmethanesulfonyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide.    (compound 87), MS (538.2 M+1, 536.1 M−1).

Example 5 Synthesis ofN-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(2,4-difluoro-phenyl)ethyl-amino]-3-(cyclopropylmethylsulfonyl)propionamideCompound 43

Step 1

2,4-Difluorobenzaldehyde (1.1 mL, 10.0 mmol) and(trifluoromethyl)trimethylsilane (1.77 mL, 12.0 mmol) were dissolved inTHF (25 mL) and then cooled to 0° C. To this, 1M TBAF in THF (76 mL, 76μmol) was added and the reaction mixture was allowed to warm to roomtemperature. After 3.25 h, 2.5M HCl (25 mL) was added. The reaction wasstirred for 1 h and then extracted with ether. The organic layer waswashed with brine and dried with Na₂SO₄. The solvent was removed underthe reduced pressure to give2,2,2-trifluoro-1-(2,4-difluoro-phenyl)ethanol (2.5 g) as a racemicmixture.

Step 2

2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanol (1.36 g, 6.4 mmol) wasdissolved in dichloromethane (25 mL) and diisopropylethylamine (DIPEA, 5mL, 28.8 mmol) was added. The resulting solution was cooled to −78° C.and trifluoromethanesulfonic anhydride (1.81 g, 6.4 mmol) was added.After 1 h, the reaction was warmed to −15° C. stirring was continued for2 h. S-trityl-L-cysteine (2.33 g, 6.4 mmol) was then added and thereaction mixture was stirred overnight. After an aqueous work-up, theorganic layer was dried with MgSO₄ then filtered through silica using acombination of ethyl acetate and acetic acid to give a diastereomericmixture of2(R)-[1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamino]-3-tritylsulfanylpropionicacid (2.47 g).

Step 3

2(R)-[1-(2,4-Difluorophenyl)-2,2,2-trifluoroethylamino]-3-tritylsulfanylpropionicacid (2.47 g, 4.4 mmol) was dissolved in a 30% TFA/30% Et₃SiH/40% CH₂Cl₂v/v/v solution (5 mL). After stirring for 1 h, toluene was added and allsolvents were removed under reduced pressure. A basic aqueous work-upwas done using 2.7 M NaOH. To the aqueuos layer, P(CH₂CH₂COOH)₃hydrochloride (126 mg, 0.44 mmol) and cyclopropylmethyl bromide (427 mL,4.4 mmol) were added. After stirring overnight, an acidic aqueouswork-up was done. The organic layer was washed with brine and dried withMgSO₄. The solvent was removed to get a diastereomeric mixture of3-cyclopropylmethylsulfanyl-2(R)-[1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamino]propionicacid (1.25 g).

Step 4

3-Cyclopropylmethylsulfanyl-2(R)-[1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamino]-propionicacid (1.25 g, 3.4 mmol), HATU (1.29 g, 3.4 mmol), DIPEA (1.48 mL, 8.5mmol) and 1-amino-cyclopropanecarbonitrile hydrochloride (403 mg, 3.4mmol) was dissolved in NMP (20 mL). After stirring overnight, Oxone™(3.14 g, 5.1 mmol) dissolved in water (7.9 mL) was added. After 1 h,more Oxone™ (3.14 g, 5.1 mmol) was added and the reaction mixture wasstirred overnight. The product was precipated from solution by theaddition of water. The precipate was purified by C18 RP-HPLC using an0.1 mM HCl and acetonitrile system to give a diastereomeric mixture ofN-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(R)-(2,4-difluoro-phenyl)ethylamino]-3-(cyclopropylmethylsulfonyl)propionamideandN-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(2,4-difluorophenyl)ethylamino]-3-(cyclopropylmethylsulfonyl)-propionamide(˜250 mg).

Approximately 50 mg of the diastereomeric mixture was then purified on aChiralcel OD-H (2 cm×25 cm) HPLC column using a mixture of IPA andhexanes and the diasteriomeric mixture was separated.

N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,4-difluorophenylethylamino)propionamide.LC-MS: 466 (M+1), 464 (M−1), 488 (M+23). ¹H-NMR (CDCl₃): 7.50 (s, 1H),7.43 (q, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 4.65 (q, 1H), 3.71 (dd,J=5.56, 4.95 Hz, 1H), 3.59 (dd, J=14.55, 6.05 Hz, 1H), 3.35 (dd,J=14.56, 4.50 Hz, 1H), 3.03 (d, 2H), 1.18 (m, 4H), 0.77 (m, 2H), 0.45(m, 2H).

Following the procedure described in Example 5 above, the followingcompounds were prepared using the appropriated fluorinated benzaldehydestarting materials.

-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,5-difluorophenylethylamino)propionamide,    (compound 37). LC-MS: 466 (M+H), 488 (M+Na), 464 (M−H), 444 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(5)-2,5-difluorophenylethylamino)propionamide,    (compound 38). LC-MS: 466 (M+H), 488 (M+Na), 464 (M−H), 444 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,3-difluorophenylethylamino)propionamide,    (compound 42). LC-MS: 466 (M+H), 488. (M+Na), 464 (M−H), 444 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,5-difluorophenylethylamino)propionamide,    (compound 63). LC-MS: 466 (M+H), 488 (M+Na), 464 (M−H), 444 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,6-difluorophenylethylamino)propionamide,    (compound 64). LC-MS: 466 (M+H), 488 (M+Na), 464 (M−H), 444 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,6-difluorophenylethylamino)propionamide,    (compound 65). LC-MS: 466 (M+H), 488 (M+Na), 464 (M−H), 444 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,3-difluorophenylethylamino)propionamide,    (compound 66). LC-MS: 466 (M+H), 488 (M+Na), 464 (M−H), 444 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,4-difluorophenylethylamino)propionamide    (compound 67). LC-MS: 466 (M+1), 464 (M−1), 488 (M+23). ¹H-NMR    (CDCl₃): 7.83 (s, 1H), 7.52 (q, 1H), 7.00 (m, 1H), 6.90 (m, 1H),    4.42 (m, 1H), 3.68 (m, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 2.89 (d,    2H), 1.28 (m, 4H), 0.75 (m, 2H), 0.41 (m, 2H).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide,    (compound 71). LC-MS: 448 (M+H), 470 (M+Na), 446 (M−H), 426 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide,    (compound 72). LC-MS: 448 (M+H), 470 (M+Na), 446 (M−H), 426 (M−HF).-   N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide,    (compound 77). LC-MS: 501 (M+H), 523 (M+Na), 499 (M−H), 479 (M−HF).    This compound was isolated as by-product in the preparation of that    gave the corresponding pyridine derivative.-   N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide,    (compound 78). LC-MS: 501 (M+H), 523 (M+Na), 499 (M−H), 479 (M−HF).    This compound was isolated as by-product in the preparation of that    gave the corresponding pyridine derivative.-   N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(5)-2-fluorophenylethylamino)propionamide,    (compound 79). LC-MS: 485 (M+H), 507 (M+Na), 483 (M−H), 463 (M−HF).-   N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide,    (compound 80). LC-MS: 485 (M+H), 507 (M+Na), 483 (M−H), 463 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,3,4-trifluorophenylethylamino)propionamide,    (compound 81). LC-MS: 484 (M+H), 506 (M+Na), 482 (M−H), 462 (M−HF).-   N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,3,4-trifluorophenylethylamino)propionamide,    (compound 82). LC-MS: 484 (M+H), 506 (M+Na), 482 (M−H), 462 (M−HF).

Example 6 Synthesis ofN-(1-cyanocyclopropyl)-1-3-(cyclopropylmethanesulfonyl)2(R)-[2,2,3,3,3-pentafluoro-1(S)-(4-fluorophenyl)propylamino]propionamideCompound 54

Step 1

To a solution of 1-bromo-4-fluorobenzene (16.5 mL, 0.15 mol) inanhydrous THF (200 mL) at −78° C., 2,2,3,3,3-pentafluoropropionic acidethyl ether (14.4 g, 75 mmol) was slowly added. After stirring for 4 hat −78° C., ethyl ether (200 mL) and sat. sol. of NH₄Cl (100 mL) wereadded. The resulting mixture was placed in a sep. funnel, shaken and theorganic phase separated. After washing with brine, the solution wasdried over magnesium sulfate. The solution was concentrated in a rotaryvapor and the residue was purified by distillation to give2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propan-1-one.

Step 2

To a solution of 2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propan-1-one(13.0 g, 53 mmol) in a mixture 1:1 of dichloromethane and toluene (160mL) at room temperature, 1M solution of S-methyl-CBS-oxazaborolidine intoluene (5.3 mL, 5.3 mmol) was added at room temperature. The reactionmixture was cooled at −78° C. and catecholborane (7.62 g, 63 mmol) wasadded. After stirring for 7 h at −78° C., a 4 M solution of HCl indioxane (18 mL) was added. After allowing the reaction mixture to warmto room temperature, water (5 mL) was added, stirred for 5 min and 10%solution of sodium metabisulfite (25 mL) was added. The heterogeneousmixture was stirred for 15 min and the solid was separated byfiltration. The solution was concentrated on rotovap to reduce theamount of dichloromethane and then the residue was diluted with hexanes(100 mL). The resulting solution was washed with a 10% solution ofsodium metabisulfite (100 mL) and brine (100 mL). After drying overmagnesium sulfate, the solution was concentrated and the crude waspurified on a silica gel column, using dichloromethane as eluent to give(R)-2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propan-1-ol as an oil (12.01g).

Step 3

A 60% suspension of NaH in oil (2.35 g, 58.8 mmol) was washed severaltimes with hexanes and after suspending it in anhydrous ethyl ether (100mL), (R)-2,2,3,3,3-pentafluoro-1-(4-fluoro-phenyl)propan-1-ol (12.0 g,49 mmol) in ether (20 mL) was added slowly at room temperature. Afterstirring for 15 min, the reaction mixture was cooled at 0° C. andtrifluoromethylsulfonyl chloride (12.38 g, 73.7 mmol) was added. Thereaction mixture was stirred for 1:30 h at 0° C., then concentratedunder reduced pressure and the residue was diluted with hexane (100 mL).The reaction mixture was washed with sat. sol. NaHCO₃, brine and driedover magnesium sulfate. After removing the solvent on rotovapor,trifluoro-methanesulfonic acid(R)-2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propyl ester was obtained asa colorless oil (16.0 g).

Step 4

To a suspension of L-trityl-cysteine (15.45 g, 42 mmol) and diisopropylethyl amine (29.3 mL, 168 mmol) in dichloromethane (350 mL), a solutionof trifluoromethanesulfonic acid(R)-2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)-propyl ester (16.0 g, 42mmol) in dichloromethane (20 mL) was added at room temperature. Thereaction mixture was stirred for 20 h and then concentrated. The residuewas dissolved in ethyl acetate (300 mL). The organic phase was washedwith cold 1N HCl (100 mL), brine and dried over magnesium sulfate. Aftersolvent evaporation, the crude was purified by flash chromatography,using a mixture 1:2 of EA/hexanes to give2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-3-tritylsulfanyl-propionicacid as an oil (6.93 g).

Step 5

To a solution of2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyepropylamino]-3-tritylsulfanylpropionicacid (6.92 g, 12 mmol) in dichloromethane (10 mL), triethylsilane (3.73mL, 23.4 mmol) and TFA (3.61 mL, 46.9 mmol) were added at roomtemperature. The reaction mixture was stirred for 4 h. The solvent andvolatiles were evaporated on rotovap, benzene was added to the residueand the mixture was evaporated again to ensure complete removal ofexcess TFA. The residue was dissolved in 1N NaOH (50 mL) and extractedwith hexanes. To the resulting solution, P(CH₂CH₂CO₂H)₃.HCl (0.343 g,1.2 mmol) was added, and a 0.2 M stock solution of2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyepropylamino]-3-mercaptopropionicacid was obtained. Step 6

To a 0.2 M stock solution of2(R)-[2,2,3,3,3-pentafluoro-1-(5)-(4-fluorophenyl)propyl-amino]-3-mercaptopropionicacid in NaOH (10 mL, 2 mmol), cyclopropylmethylbromide (0.270 g, 2 mmol)was added. After stirring the reaction mixture for 5 h at roomtemperature, 1M HCl solution was added until pH 2-3. The reactionmixture was extracted with ethyl acetate and the combined organicextracts were washed with brine and dried over sodium sulfate andconcentrated to give3-cyclopropylmethanesulfanyl-2(R)-[2,2,3,3,3-pentafluoro-1-(5)-(4-fluoro-phenyl)propylamino]-propionicacid as a foam (0.678 g).

Step 7

To a solution of3-cyclopropylmethanesulfanyl-2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluoro-phenyl)propylamino]-propionicacid (0.670 g, 1.67 mmol) in DMF (3 mL),1-amino-cyclopropanecarbonitrile hydrogen chloride salt (0.236 g, 3mmol), HATU (0.760 g, 2 mmol) and diisopropyl ethyl amine (0.87 mL, 5mmol) were added. After stirring for 4 h, the reaction mixture wasdiluted with ethyl acetate (20 mL) and then washed with a sat. solutionof NaHCO₃ (10 mL), water (10 mL) and brine (10 mL). The crude solutionwas dried over sodium sufate. After evaporation of the solvent, thecrude oil was purified by flash chromatography, using a mixture 1:1 ofEA/Hexanes to giveN-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfanyl)-2(R)-(3,3,3,2,2-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamideas a light yellow solid (0.558 g).

Step 8

To a solution ofN-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfanyl)-2(R)-(3,3,3,2,2-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide(0.540 g, 1.16 mmol) in N-methylpyrrolidinone (4 mL), a solution ofOXONE (1.06 g, 1.74 mmol) in water (3.8 mL) was added at roomtemperature. The heterogeneous mixture was stirred overnight at roomtemperature. After cooling at 0° C., water (20 mL) was added and mixturewas stirred for 15 min. The solid was separated by filtration and washedwith fresh water. The crude solid was purified by flash chromatographyusing a mixture of EA/H as eluent to give title compound as a whitesolid (0.105 g, 19%). ¹H NMR (DMSO-d₆): δ 8.94 (1H, s), 7.44 (2H, dd),7.22 (21-1, t), 4.53 (1H, m), 3.68 (1H, q), 3.66 (1H, m), 3.30 (2H, m),3.12 (2H, m), 1.30 (2H, m), 1.00 (1H, m), 0.90 (1H, m), 0.58 (2H, m),0.47 (1H, m), 0.30 (2H, m). LC/MS, M+1: 498.4, M−1: 496.3.

Example 7 Synthesis ofN-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-[2,2,3,3,3-pentafluoro-1(S)-(4-fluorophenyl)propylamino]propionamideCompound 50

Step 1

To a 0.2 M stock solution of3-mercapto-2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-propionicacid in NaOH (10 mL, 2 mmol), 2-chloromethylpyridine (0.328 g, 2 mmol)and 1N solution of NaOH (1 mL) were added. After stirring the reactionmixture for 5 h at room temperature, 1M HCl solution was added until pH5-6. The mixture was extracted with ethyl acetate and the combinedorganic extracts were washed with brine and dried over sodium sulfateand concentrated to giveN-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfanyl)-2(R)-[3,3,3,2,2-pentafluoro-1(S)-(4-fluorophenyl)propylamino]-propionamideas a foam (0.692 g) which was converted to the title compound asdescribed in Example 6 above.

¹HNMR (DMSO-d₆): δ 8.97 (1H, s), 8.60 (1H, m), 7.88 (1H, m), 7.47 (4H,m), 7.24 (2H, t), 4.74 (2H, s), 4.58 (1H, m), 3.73 (2H, m), 3.44 (2H,m), 1.33 (2H, m), 0.93 (1H, m), 0.53 (1H, m). LC/MS, M+1: 535.3; M−1:533.4 and compound 51(15%) as a by-product. LC/MS, M+1: 551.3, M−1:549.4.

Proceeding as described in Example 7 above but substituting2-chloromethylpyridine with 3-chloromethylpyridine providedN-(1-cyanocyclopropyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-(3,3,3,2,2-pentafluoro-1(S)-4-fluorophenylpropylamino)-propionamide(compound 52), ¹H NMR (DMSO-d₆): δ 9.00 (1H, s), 8.61 (1H, m), 8.57 (1H,m), 7.80 (1H, m), 7.48 (3H, m), 7.24 (211, t), 4.64 (2H, dd), 4.58 (1H,m), 3.82 (1H, t), 3.70 (111, m), 3.42 (1H, m), 3.30 (111, m), 1.20 (2H,m), 0.90 (1H, m), 0.50 (1H, m). LC/MS, M+1: 535.3, M−1: 533.2. Compound53 was obtained as a by-product (5%). LC/MS, M+1: 551.3, M−1: 549.3; and

-   N-(1-cyanocyclopropyl)-3-(1-oxopyridin-3-ylmethanesulfonyl)-2(R)-(3,3,3,2,2-pentafluoro-1(S)-4-fluorophenylpropylamino)-propionamide    (compound 53)

Proceeding as described in Example 7 above but substituting2-chloromethyl-pyridine with 5-methylisoxazol-3-ylmethyl chlorideprovideN-(1-cyanocyclopropyl)-3-(5-methylisoxazol-3-ylmethanesulfonyl)-2(R)-(3,3,3,2,2-pentafluoro-1(S)-4-fluorophenylpropyl-amino)-propionamide(compound 59), ¹HNMR (DMSO-d₆): 8.97 (1H, s), 7.46 (2H, dd), 7.24 (211,dd), 6.32 (1H, s), 4.74 (21-1, d), 4.55 (1H, m), 3.70 (211, m), 3.44(2H, m), 2.45 (311, s), 1.33 (211, m), 0.92 (1H, m), 0.52 (1H, m).LC\MS: M−1: 536.9, M+1: 539.2

Proceeding as described in Example7N-(1-cyanocyclopropyl)-3-(2-pyridin-2-ylethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylethylamino)propionamidewas prepared (compound 88), ¹HNMR (DMSO-d₆): 8.97 (111, s), 8.75 (1H,d), 8.28 (1H, m), 7.82 (1H, d), 7.72 (1H, m), 7.46 (211, dd), 7.24 (2H,dd), 4.74 (1H, m), 4.00-3.30 (7H, bm), 1.33 (211, m), 0.92 (111, m),0.52 (111, m) LC\MS: M−1: 547.5, M+1: 549.3

Example 8 Synthesis ofN-(1-cyanocyclopropyl)-3-(2-trifluoromethylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamideCompound 35

2-(Trifluoromethyl)benzyl bromide (0.50 mmol) was dissolved in dioxane(3 mL) and a 0.16 M stock solution of3-mercapto-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-propionicacid (4.7 mL, 0.75 mmol) in 1.0 M aqueous sodium hydroxide/0.032 Mtris(2-carboxyethyl)phosphine hydrochloride was added. After stirringovernight, the reaction mixture was concentrated to half the volume andthen diluted with water and washed with heptane. Ethyl acetate (5 mL)was added and the two phase mixture was placed in an ice/water bath andthe pH was adjusted to 3 with 3.0 M hydrochloric acid. The aqueous phasewas extracted with EtOAc and the combined organic extracts were washedwith brine, dried over MgSO₄, and concentrated. The residue wasdissolved in DMF (2 mL) and 1-aminocyclopropanecarbonitrilehydrochloride (64 mg, 0.54 mmol), DIPEA (260 4, 1.5 mmol), HATU (191 mg,0.50 mmol) were added and the reaction mixture was stirred overnight.After concentrating the residue was dissolved in EtOAc and washed with1.0 MKHSO₄, saturated NaHCO₃, and brine and dried over anhydrous MgSO₄.Solvent was removed and the residue was dissolved in acetonitrile (3 mL)and a 0.50 M aqueous solution of Oxone™ (1.5 mL, 0.75 mmol) was added.After stirring overnight, the reaction mixture was diluted with waterand extracted with EtOAc. The combined organic extracts were washed withbrine, dried over anhydrous MgSO₄ and concentrated. The residue waspurified by flash chromatography on silica gel to give the titlecompound (55 mg) as a white solid mixture of diastereomers in 80% de(1S,2R)>(1R,2R). (compound 35), LC-MS: 552(M+1), 551(M−1), 574(M+23),¹H-NMR (DMSO): 0.80 (m, 1H), 1.05 (m, 1H), 1.38 (m, 2H), 3.38 (m, 1H),3.68 (m, 2H), 3.80 (m, 1H), 4.40 (m, 1H), 4.88 (q, 2H), 7.25 (t, 2H),7.47 (dd, 2H), 7.65 (m, 2H), 7.75 (m, 1H), 7.82 (d, 1H), 9.10 (s, 1H).

Following the procedure described above the following compounds wereprepared.

-   N-(1-cyanocyclopropyl)-3-(2-methylpropylsulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide    (compound 29), LC-MS: 450(M+1), 448(M−1), 472(M+23).-   N-(1-cyanocyclopropyl)-3-(2-trifluoromethoxyphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide    (compound 36), LC-MS: 568(M+1), 566(M−1), 590(M+23).-   N-(1-cyanocyclopropyl)-3-(tetrahydropyran-2RS-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide    (compound 56),-   LC-MS: 492(M+1), 490(M−1), 514(M+23).

N-(1-cyanocyclopropyl)-3-(2,6-dichlorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide(compound 57), LC-MS: 552:554:556 ratio 9:6:1(M+1); 550, 552, 554 ratio9:6:1(M−1); 574, 576, 578 ratio 9:6:1(M+23).

-   N-(1-cyanocyclopropyl)-3-(1-ethyl-2,5-dioxopyrrolidin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide    (compound 89)-   LC-MS: 553(M+1), 551(M−1), 575(M+23).

Example 9 Synthesis ofN-(1-cyanocyclopropyl)-3-(5-methylisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamideCompound 28

3-(Bromomethyl)-5-methylisoxazole (0.5 mmol) was dissolved inacetonitrile (1.5 mL) and a 0.50 M stock solution of3-mercapto-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethyl-amino]propionicacid (1.5 mL, 0.75 mmol) in 2.0 M aqueous sodium hydroxide was added.After 2 h, water (2 mL) and acetonitrile (2 mL) were added and the twophase mixture was washed with heptane. The heptane extract was discardedand the aqueous phase was placed in an ice/water bath and the pH wasadjusted to 3 with 1.0 M aqueous KHSO₄. The organic phase was separatedand the aqueous phase was extracted with EtOAc. The combined organicextracts were washed with brine, dried over anhydrous MgSO₄, andconcentrated. The residue was dissolved in acetonitrile (3 mL) and1-aminocyclopropanecarbonitrile hydrochloride (88 mg, 0.74 mmol), DIPEA(390 4, 2.2 mmol) and HATU (287 mg, 0.75 mmol) were added. After 2 h,the reaction mixture was diluted with and a 0.50 M aqueous solution ofOxone™ (3.0 mL, 1.5 mmol) was added. After stirring the reaction mixtureat 50° for 2 h, water (5 mL) was added and the reaction mixture wasconcentrated to remove acetonitrile. The aqueous layer was extractedwith EtOAc, and the combined organic extracts were washed with 1.0 Maqueous KHSO₄, 1:1 water:saturated NaHCO₃, and brine, and dried overanhydrous MgSO₄. After concentration, the residue through a plug ofsilica gel using EtOAc eluent and collected all material with R_(f)>0.5.After concentration the residue was purified by flash chromatography togive title compound (63 mg) as a white solid mixture of diastereomers,85% de, (1′S,2R)>(1′R,2R). LC-MS: 489(M+1), 487(M−1), 511(M+23). ¹H-NMR(DMSO): 0.74 (m, 1H), 1.01 (m, 1H), 1.36 (m, 2H), 2.44 (s, 3H), 3.36 (m,1H), 3.68 (m, 2H), 3.75 (m, 1H), 4.41 (m, 1H), 4.77 (q, 2H), 6.33 (s,1H), 7.25 (t, 2H), 7.47 (dd, 2H), 9.04 (s, 1H).

Following the procedure described above, the following compounds wereprepared:

-   N-(1-cyanocyclopropyl)-3-(benzo[1.2.5]thiadiazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide    (compound 26), LC-MS: 542(M+1), 540(M−1), 564(M+23).-   N-(1-cyanocyclopropyl)-3-(benzothiazol-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide    (compound 27), LC-MS: 541(M+1), 539(M−1), 563(M+23).-   N-(1-cyanocyclopropyl)-3-(cyclobutylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide    (compound 30), LC-MS: 462(M+1), 460(M−1), 484(M+23).-   N-(1-cyanocyclopropyl)-3-(quinolin-8-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide    (compound 41), LC-MS: 535(M+1), 533(M−1), 557(M+23).-   N-(1-cyanocyclopropyl)-3-(5-methyl-3-phenylisoxazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide    (compound 44),-   LC-MS: 565(M+1), 563(M−1), 587(M+23).-   N-(1-cyanocyclopropyl)-3-(4-methyl-2-phenyl-[1.2.3]triazol-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)-propionamide    (compound 45), LC-MS: 565(M+1), 563 (M−1), 487(M+23).-   N-(1-cyanocyclopropyl)-3-(2-cyanophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide    (compound 46), LC-MS: 509(M+1), 507(M−1), 531(M+23).-   N-(1-cyanocyclopropyl)-3-(3-methoxycarbonylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide    (compound 47),-   LC-MS: 542(M+1), 540(M−1), 4564(M+23).-   N-(1-cyanocyclopropyl)-3-(3-methoxycarbonylfuran-2RS-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide    (compound 58),-   LC-MS: 532(M+1), 530(M−1), 554(M+23).

Example 10 Synthesis ofN-(1-cyanocyclopropyl)-2(S)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]-4-(pyridin-2-ylsulfonyl)butyramide

Step 1

3(S)-Aminodihydrofuran-2-one (12.4 g, 68.2 mmol) was added in dioxane(136 mL) and 1N NaOH (136 mL) was added to give a clear solution. Thereaction mixture was cooled in ice-water bath and Boc-anhydride (16.35g, 74.9 mmol) was added in portions. The reaction mixture was warmed toambient temp. overnight and after concentrating it to approx. 150 mL,ethyl acetate (150 mL) was added. After acidifying the reaction mixtureto pH 4 with concentrated aqueous KHSO₄, the organic layer was separatedand concentrated to give (2-oxotetrahydro-furan-3(R)-yl)-carbamic acidtert-butyl ester as a white solid which was used without furtherpurification.

Step 2

Clean sodium metal (0.205 g, 8.95 mmol) was added, in portions, toanhydrous methanol (20 mL) in a thick walled tube . The suspension wasstirred under anhydrous nitrogen until all the metal had dissolved, thenpyridine-2-thiol (1.0 g, 8.95 mmol) was added. After stirring for 20min, (2-oxotetrahydro-furan-3(R)-yl)-carbamic acid tert-butyl ester (1.8g, 8.95 mmol) was added as a solid and the tube was capped and heated to100° C. for 16 h. The reaction mixture was concentrated, then purifiedvia flash chromatography (MeOH, CH₂Cl₂ as eluent) to give2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyric acid (0.75g) as a clear oil.

Step 3

To 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyric acid(0.75 g, 2.40 mmol) in methanol (16 mL) and toluene (50 mL) was added a2.0M solution of (trimethylsilyl)diazomethane (3.12 mmol) dropwise.After 3 h, the reaction mixture was concentrated to give methyl2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyrate as anoily residue which was used without further purification.

Step 4

To methyl 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyrate(0.75 g, 2.4 mmol) in THF (5 mL) was added methanesulfonic acid (6.9 g,7.2 mmol) in one portion. The solution was stirred for 16 h and thecrude reaction mixture was concentrated to give methyl2(S)-amino-4-(pyridin-2-ylsulfanyl)butyrate as the mesylate salt whichwas used directly in the next step.

Step 5

Methyl 2(5)-amino-4-(pyridin-2-ylsulfanyl)butyrate (0.610 g, 2.33 mmol),2,2,2,4′-tetrafluoroacetophenone (0.393 g, 2.05 mmol), and DIPEA (1.24g, 9.63 mmol) were combined in CH₂Cl₂ (10 mL). TiCl₄ (1.90 mmol inCH₂Cl₂) was added dropwise over a 5 min period. The resulting darksolution was stirred for 3 h at which time sodium cyanoborohydride (6.35mmol) in methanol (5 mL) was added in one portion, and the brownsolution stirred for an additional 45 min. The reaction mixture wasdiluted with ethyl acetate, poured onto a bed of MgSO₄ and filtered.Concentration and purification by flash chromatography (50% ethylacetate/hexanes) afforded4-(pyridin-2-ylsulfanyl)-2(5)[2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino]-butyricacid methyl ester as a mixture of diastereomers.

Step 6

4-(Pyridin-2-ylsulfanyl)-2(S)-[2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino]butyricacid methyl ester was dissolved in methanol (2 mL) and 1N NaOH (1.2 mL)was added. After stirring for 2 h, methanol was removed and the aqueouslayer was acidified to pH 5. After extracting with ethyl acetate theorganic layer was dried and concentrated to give4-(pyridin-2-ylsulfanyl)-2(S)-[2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino]butyricacid as an oil which was then converted to the title compound asdescribed above. MS (485.5 M+1)

BIOLOGICAL EXAMPLES Example 1 Cathepsin B Assay

Solutions of test compounds in varying concentrations were prepared in10 μl of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid(BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; anddithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in 25 μLof assay buffer) was added to the dilutions. The assay solutions weremixed for 5-10 seconds on a shaker plate, covered and incubated for 30min at room temperature. Z-FR-AMC (20 nMoles in 254 of assay buffer) wasadded to the assay solutions and hydrolysis was followedspectrophotometrically at (2 460 nm) for 5 min. Apparent inhibitionconstants (K_(i)) were calculated from the enzyme progress curves usingstandard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin B inhibitory activity.

Example 2 Cathepsin K Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).Human cathepsin K (0.0906 pMoles in 25 μL of assay buffer) was added tothe dilutions. The assay solutions were mixed for 5-10 seconds on ashaker plate, covered and incubated for 30 min at room temperature.Z-Phe-Arg-AMC (4 nMoles in 25 μL of assay buffer) was added to the assaysolutions and hydrolysis was followed spectrophotometrically at (k 460nm) for 5 min. Apparent inhibition constants (K_(i)) were calculatedfrom the enzyme progress curves using standard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin K inhibitory activity.

Example 3 Cathepsin L Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).Human cathepsin L (0.05 pMoles in 25 μL of assay buffer) was added tothe dilutions. The assay solutions were mixed for 5-10 seconds on ashaker plate, covered and incubated for 30 min at room temperature.Z-Phe-Arg-AMC (1 nMoles in 25 μl, of assay buffer) was added to theassay solutions and hydrolysis was followed spectrophotometrically at (λ460 nm) for 5 min. Apparent inhibition constants (K_(i)) were calculatedfrom the enzyme progress curves using standard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin L inhibitory activity.

Example 4 Cathepsin S Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 4, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM);β-mercaptoethanol, 2.5 mM; and BSA, 0.00%. Human cathepsin S (0.05pMoles in 25 μL of assay buffer) was added to the dilutions. The assaysolutions were mixed for 5-10 seconds on a shaker plate, covered andincubated for 30 min at room temperature. Z-Val-Val-Arg-AMC (4 nMoles in25 μL of assay buffer containing 10% DMSO) was added to the assaysolutions and hydrolysis was followed spectrophotometrically (at λ460nm) for 5 min. Apparent inhibition constants (K_(i)) were calculatedfrom the enzyme progress curves using standard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin S inhibitory activity of <or =100 nm.

Example 5

Cathepsin F Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100mM); DTT, 2.5 mM; and BSA, 0.01%. Human cathepsin F (0.1 pMoles in 25 μLof assay buffer) was added to the dilutions. The assay solutions weremixed for 5-10 seconds on a shaker plate, covered and incubated for 30min at room temperature. Z-Phe-Arg-AMC (2 nmoles in 25 μL of assaybuffer containing 10% DMSO) was added to the assay solutions andhydrolysis was followed spectrophotometrically (at λ460 nm) for 5 min.Apparent inhibition constants (K_(i)) were calculated from the enzymeprogress curves using standard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin F inhibitory activity.

FORMULATION EXAMPLES Example 1 Representative pharmaceuticalformulations Containing a Compound of Formula (I)

ORAL FORMULATION Compound of Formula (I) 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of Formula (I) 0.1-10 mg DextroseMonohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05 mg SodiumHydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of Formula (I)  1% MicrocrystallineCellulose 73% Stearic Acid 25% Colloidal Silica  1%

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

1. A compound of Formula (I):

R¹ is hydrogen, alkyl, or haloalkyl; R² is hydrogen, alkyl, orhaloalkyl; or R¹ and R² taken together with the carbon atom to which R¹and R² are attached form cycloalkylene optionally substituted with oneto four fluoro, piperidin-4-yl wherein the nitrogen atom of thepiperidinyl ring is substituted with alkyl, haloalkyl, or cycloalkyl,tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl,1,1-dioxohexahydrothiopyran-4-yl, or —CH₂—O—CH₂—; R³ is-alkylene-SO₂-alkyl, -alkylene-SO₂-haloalkyl, -alkylene-SO₂-cycloalkyl,-alkylene-SO₂-cycloalkylalkyl, -alkylene-SO₂-aryl,-alkylene-SO₂-aralkyl, -alkylene-SO₂-heterocycloalkyl,-alkylene-SO₂-heterocycloalkylalkyl, -alkylene-SO₂-heteroaryl,-alkylene-SO₂-heteroaralkyl, -alkylene-SO₂-haloalkylene-aryl or-alkylene-SO₂-haloalkylene-heteroaryl wherein the aromatic or alicyclicring in R³ is optionally substituted with one, two, or three R^(a)independently selected from alkyl, alkylsulfonyl, haloalkyl, alkoxy,hydroxy, hydroxyalkyl, haloalkoxy, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, amino, alkylamino,dialkylamino, aminocarbonyl, or acyl and further wherein the aromaticring in R^(a) is optionally substituted with one, two, or three R^(b)independently selected from alkyl, alkoxy, alkylsulfonyl, hydroxy, orhalo; R⁴ is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, orheterocycloalkyl attached via a carbon ring atom wherein the aromatic oralicyclic ring in R⁴ is optionally substituted by one, two, or threeR^(f) independently selected from alkyl, halo, hydroxy, alkoxy,alkylcarbonyl, alkylsulfonyl, alkylsulfonylamino, aminocarbonyl,haloalkyl, haloalkoxy, carboxy, or alkoxycarbonyl; R^(4′) isdifluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl,chlorodifluoromethyl, 1,1-dichloro-2,2,2-trifluoroethyl,1,1,2,2-tetrafluoroethyl, trichloromethyl, dichlorofluoromethyl,1,1,2,2,3,3,3-heptafluoropropyl, or 1,1,2,2,3,3-hexafluoropropyl, or apharmaceutically acceptable salt thereof provided that: (a) when R¹ andR² taken together with the carbon atom to which R¹ and R² are attachedform cyclopropylene, R³ is phenylmethanesulfonylmethyl,cyclopropylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl,2-difluoromethoxyphenylmethanesulfonylmethyl, or2-trifluoromethylpyridin-6-methanesulfonylmethyl, R⁴ is phenyl,4-hydroxyphenyl, 3-bromophenyl, 4-fluorophenyl,3-chloro-4-hydroxyphenyl, 3,4-difluorophenyl, or 3,4,5-trifluorophenyl,then R^(4′) is not trifluoromethyl or difluoromethyl; (b) when R¹ and R²taken together with the carbon atom to which R¹ and R² are attached formcyclopropylene, R³ is phenylmethanesulfonylmethyl,difluoromethoxyphenylmethanesulfonylmethyl, orcyclopropylmethanesulfonylmethyl, R⁴ is furan-2-yl, indol-3-yl,thiophen-2-yl, 1-methylpyrrol-2-yl, pyridin-2-yl, thiophen-3-yl or1-oxo-1-methylpyrrol-2-yl, then R^(4′) is not difluoromethyl ortrifluoromethyl; (c) when R¹ and R² taken together with the carbon atomto which R¹ and R² are attached form 1,1-dioxohexahydrothiopyran-4-yl,R³ is phenylmethanesulfonylmethyl, 4-fluorophenylmethanesulfonylmethyl,or difluoromethoxyphenylmethanesulfonylmethyl, then R^(4′) is nottrifluoromethyl; and (d) when R^(I) and R² taken together with thecarbon atom to which R^(I) and R² are attached form tetrahydropyran-4-ylor tetrahydrothiopyran-4-yl, R³ is cyclopropylmethanesulfonylmethyl ordifluoromethoxyphenylmethanesulfonylmethyl, R⁴ is 4-fluorophenyl, thenR^(4′) is not trifluoromethyl.
 2. The compound of claim 1 wherein R³ is-alkylene-SO₂-haloalkylene-heteroaryl.
 3. The compound of claim 1wherein: R¹ and R² are cyclopropylene; R³ is4-CF₃-pyridin-3-ylmethanesulfonylmethyl,pyridin-3-ylmethanesulfonylmethyl, pyridazin-3-ylmethanesulfonylmethyl,2-CF₃-furan-5-ylmethanesulfonylmethyl,pyrimidin-5-ylmethanesulfonylmethyl,2-CH₃-thiazol-4-ylmethanesulfonylmethyl,pyridin-4-ylmethane-sulfonylmethyl, pyrimidin-4-ylmethanesulfonylmethyl,2-(1-oxopyrrol-1-yl)ethanesulfonyl-methyl,cyclopropylmethanesulfonylmethyl,3,3,3-trifluoropropane-1-sulfonylmethyl,2-CF₃-pyridin-5-ylmethanesulfonylmethyl,4-[1.2.4]-triazol-1-ylphenylmethanesulfonylmethyl,2-(2-oxo-2,3-dihydrobenzimidazol-1-yl)-ethanesulfonylmethyl,5-oxopyrrolidin-2-ylmethane-sulfonylmethyl,2-F-pyridin-3-ylmethanesulfonylmethyl,3-CH₃-oxetan-3-ylmethanesulfonyl-methyl, 2-phenylethanesulfonylmethyl,fluoro-pyridin-2-ylmethanesulfonylmethyl,fluoro-pyrazin-2-ylmethanesulfonylmethyl,difluoro-pyridin-2-ylmethanesulfonylmethyl,difluoro-pyridin-3-ylmethanesulfonylmethyl,quinolin-2-ylmethanesulfonylmethyl,benzo[1.2.5]thiadiazol-4-ylmethanesulfonylmethyl,benzothiazol-2-ylmethanesulfonylmethyl,5-methylisoxazol-3-ylmethanesulfonylmethyl,2-methylpropyl-sulfonylmethyl, 2,6-difluorophenylmethanesulfonylmethyl,2,4-difluorophenylmethane-sulfonylmethyl,quinolin-3-ylmethanesulfonylmethyl,4,4,4-trifluorobutyl-1-sulfonylmethyl,2-CF₃-phenylmethanesulfonylmethyl, 2-CF₃O-phenylmethanesulfonylmethyl,2-pyridin-2-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl,quinolin-8-ylmethane-sulfonylmethyl,5-methyl-3-phenylisoxazol-4-ylmethanesulfonylmethyl,4-methyl-2-phenyl-[1.2.3]triazol-5-ylmethanesulfonylmethyl,2-cyanophenylmethanesulfonylmethyl,3-methoxycarbonylphenylmethanesulfonylmethyl,pyridin-2-ylmethanesulfonylmethyl,1-oxopyridin-2-ylmethanesulfonylmethyl,1-oxopyridin-3-ylmethanesulfonylmethyl,quinoxalin-2-ylmethanesulfonylmethyl,tetrahydropyran-2RS-ylmethanesulfonylmethyl,2,6-dichloro-phenylmethanesulfonylmethyl,3-methoxycarbonyl-furan-2-yl-methanesulfonylmethyl,5-methylisoxazol-3-ylmethanesulfonylmethyl,2,2-dimethylpropylsulfonylmethyl, ethanesulfonylmethyl,methanesulfonylmethyl, propane-1-sulfonylmethyl,1H-indol-2-ylmethanesulfonylmethyl,2-(1H-indol-3-yl)ethanesulfonylmethyl,2,2,2-trifluoroethanesulfonylmethyl,benzisoxazol-3-ylmethanesulfonylmethyl,2-tert-butyl-[1.3.4]thiadiazol-5-ylmethanesulfonylmethyl,2,4,6-trifluorophenylmethanesulfonylmethyl,2-pyridin-2-ylethanesulfonylmethyl,1-ethyl-2,5-dioxopyrrolidin-3-ylmethanesulfonylmethyl orbenzisoxazol-3-ylmethanesulfonylmethyll; and R⁴ is 4-fluorophenyl,2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, or3,5-difluorophenyl.
 4. The compound of claim 1 wherein: R^(4′) isdifluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl,chlorodifluoromethyl, 1,1-dichloro-2,2,2-trifluoroethyl,1,1,2,2-tetrafluoroethyl, trichloromethyl, dichlorofluoromethyl,1,1,2,2,3,3,3-heptafluoropropyl, or 1,1,2,2,3,3-hexafluoropropyl; and R⁴is hydrogen.
 5. The compound of claim 1 wherein: R^(4′) isdifluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl,chlorodifluoromethyl, 1,1-dichloro-2,2,2-trifluoroethyl,1,1,2,2-tetrafluoroethyl, trichloromethyl, dichlorofluoromethyl,1,1,2,2,3,3,3-heptafluoropropyl, or 1,1,2,2,3,3-hexafluoropropyl; and R⁴is alkyl.
 6. The compound of claim 1 wherein: R^(4′) is difluoromethyl,trifluoromethyl, 1,1,2,2,2-pentafluoroethyl, chlorodifluoromethyl,1,1-dichloro-2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl,trichloromethyl, dichlorofluoromethyl, 1,1,2,2,3,3,3-heptafluoropropyl,or 1,1,2,2,3,3-hexafluoropropyl; and R⁴ is haloalkyl.
 7. The compound ofclaim 1, 11, 5, or 6 wherein R³ is3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl;2-CF₃-methylphenylmethane-sulfonylmethyl,3-CF₃pyridin-2-ylmethanesulfonylmethyl,2-F-furan-5-ylmethanesulfonyl-methyl,2-methylthiazol-4-ylmethanesulfonylmethyl,tetrahydropyran-4-ylmethane-sulfonylmethyl,1,1-dioxo-1λ⁶-hexahydrothiopyran-4-ylmethanesulfonylmethyl,1-ethylpiperidin-4-ylmethanesulfonylmethyl,2-oxo-tetrahydropyrimidin-4-ylmethane-sulfonylmethyl,1-ethyl-2-oxopiperidin-4-ylmethanesulfonylmethyl,1-acetylpiperidin-4-ylmethanesulfonylmethyl,1-ethoxycarbonylpiperidin-4-ylmethanesulfonylmethyl,1-methylsulfonylpiperidin-4-ylmethanesulfonylmethyl,1-cyclopropylpiperidin-4-ylmethane-sulfonylmethyl,1-acetylazetidin-3-ylmethanesulfonylmethyl,1-ethoxycarbonylazetidin-3-ylmethanesulfonylmethyl,1-methylsulfonylazetidin-3-ylmethanesulfonylmethyl,1-ethylazetidin-3-ylmethanesulfonylmethyl,1-cyclopropylazetidin-3-ylmethanesulfonylmethylfuran-2-ylmethanesulfonylmethyl,difluoro-(4-fluorophenyl)methanesulfonylmethyl,difluoro-(pyrazin-2-yl)methanesulfonylmethyl,difluoro-(2-difluoromethoxyphenyl)-methanesulfonylmethyl,1-acetylpiperidin-4-ylsulfonylmethyl,1-ethoxycarbonylpiperidin-4-ylsulfonylmethyl,1-cyclopropyllpiperidin-4-ylsulfonylmethyl,2-(pyridin-2-ylmethanesulfonyl-methyl,2-(pyridin-3-ylmethanesulfonylmethyl,2-(pyridin-4-yl)ethanesulfonylmethyl,3-(pyridin-2-yl)propanesulfonylmethyl,2,6-difluorophenylmethanesulfonyl,[1.3.5]triazin-2-ylmethanesulfonylmethyl,[1.3.4]thiadiazol-2-ylmethanesulfonylmethyl,oxazol-5-ylmethane-sulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl,4-fluorophenylmethanesulfonylmethyl,4-aminocarbonylphenylmethanesulfonylmethyl,4-piperazin-4-ylphenylmethanesulfonylmethyl,5-fluoroindol-3-ylmethanesulfonylmethyl,4,6-difluoroindol-3-ylmethanesulfonylmethyl,1-methylindol-3-ylmethanesulfonylmethyl,4-fluoroindol-3-ylmethanesulfonylmethyl,2-(5-fluoroindol-3-ylmethanesulfonylmethyl,2-(4,6-difluoroindol-3-ylmethanesulfonylmethyl,2-(1-methylindol-3-ylmethanesulfonylmethyl,2-(4-fluoroindol-3-yl)ethanesulfonylmethyl,2-quinolin-3-ylethanesulfonylmethyl,2-quinolin-2-ylethanesulfonylmethyl,isoquinolin-3-ylmethane-sulfonylmethyl,2-(isoquinolin-3-yl)ethanesulfonylmethyl,2,4-difluoropyridin-3-ylmethane-sulfonylmethyl,3,4-difluoropyridin-4-ylmethanesulfonylmethyl,2-(2,4-difluoropyridin-3-yl)ethanesulfonylmethyl,2-(3,4-difluoropyridin-4-ylmethanesulfonylmethyl,fluoro-(2,4-difluoropyridin-3-ylmmethanesulfonylmethyl,fluoro-(3,4-difluoropyridin-4-yl)methane-sulfonylmethyl,2,4-diCF₃pyridin-3-ylmethanesulfonylmethyl,3,4-diCF₃pyridin-4-ylmethane-sulfonylmethyl,2-(2,4-diCF₃pyridin-3-ylmethanesulfonylmethyl,2-(3,4-diCF₃pyridin-4-ylmethanesulfonylmethyl,fluoro-(2,4-diCF₃pyridin-3-yl)methanesulfonylmethyl,fluoro-(3,4-diCF₃pyridin-4-yl)methanesulfonylmethyl,4-F-pyridin-3-ylmethanesulfonylmethyl,3-F-pyridin-5-ylmethanesulfonylmethyl,2-F-pyridin-5-ylmethanesulfonylmethyl,2-F-pyridin-3-ylmethanesulfonylmethyl,5-F-pyridin-2-ylmethanesulfonylmethyl,4-F-pyridin-2-ylmethane-sulfonylmethyl,4-F-1-oxopyridin-3-ylmethanesulfonylmethyl,3-F-1-oxopyridin-5-ylmethane-sulfonylmethyl,2-F-1-oxopyridin-5-ylmethanesulfonylmethyl,2-F-1-oxopyridin-3-ylmethane-sulfonylmethyl,5-F-1-oxopyridin-2-ylmethanesulfonylmethyl,4-F-1-oxopyridin-2-ylmethane-sulfonylmethyl,4-CF₃-pyridin-2-ylmethanesulfonylmethyl,3-CF₃-pyridin-5-ylmethane-sulfonylmethyl,3-F-pyridin-2-ylmethanesulfonylmethyl,2-CF₃-pyridin-3-ylmethane-sulfonylmethyl,4-CF₃-1-oxopyridin-2-ylmethanesulfonylmethyl,3-CF₃-1-oxopyridin-5-ylmethanesulfonylmethyl,3-F-1-oxopyridin-2-ylmethanesulfonylmethyl,2-CF₃-1-oxopyridin-3-ylmethanesulfonylmethyl,5-CF₃-1-oxopyridin-2-ylmethanesulfonylmethyl,2-CH₃-pyridin-6-ylmethanesulfonylmethyl,3-CH₃-pyridin-2-ylmethanesulfonylmethyl,4-CH₃-pyridin-3-ylmethanesulfonylmethyl,3-CH₃-pyridin-4-ylmethanesulfonylmethyl,2-(2-CH₃-pyridin-6-ylmethanesulfonylmethyl,2-(3-CF₃-pyridin-2-ylmethanesulfonylmethyl,2-(4-CF₃-pyridin-3-yl)ethanesulfonylmethyl,2-(3-CF₃-pyridin-4-yl)ethanesulfonylmethyl,2-C₂H₅-pyridin-6-ylmethanesulfonylmethyl,3-C₂H₅-pyridin-2-ylmethanesulfonylmethyl,4-C₂H₅-pyridin-3-ylmethanesulfonylmethyl,3-C₂H₅-pyridin-4-ylmethanesulfonylmethyl,2-(2-C₂H₅-pyridin-6-ylmethanesulfonylmethyl,2-(3-C₂H₅-pyridin-2-ylmethanesulfonylmethyl,2-(4-C₂H₅-pyridin-3-ylmethanesulfonylmethyl,2-(3-C₂H₅-pyridin-4-yl)ethanesulfonylmethyl,2-(2-CH₃-pyridin-3-ylmethanesulfonylmethyl,2-CF₃-pyridin-3-ylmethanesulfonylmethyl,2-(3-CF₃-pyridin-4-ylmethanesulfonylmethyl,3-CF₃-pyridin-4-ylmethanesulfonylmethyl,cinnolin-3-ylmethane-sulfonylmethyl,2-(cinnolin-3-yl)ethanesulfonylmethyl,phthalazin-1-ylmethanesulfonylmethyl,2-(phthalazin-1-ylmethanesulfonylmethyl,2-(quinoxalin-2-yl)ethanesulfonylmethyl,quinazolin-2-ylmethanesulfonylmethyl,2-(quinazolin-2-yl)ethanesulfonylmethyl,[1,8]naphthyridin-2-ylmethanesulfonylmethyl,2-([1,8]naphthyridin-2-ylmethanesulfonylmethyl,[1,8]naphthyridin-3-ylmethanesulfonylmethyl,2-([1,8]naphthyridin-3-ylmethanesulfonylmethyl,3-Cl-pyridin-2-ylmethanesulfonylmethyl,4-Cl-pyridin-3-ylmethanesulfonylmethyl,3-Cl-pyridin-4-ylmethane-sulfonylmethyl,3-F-pyridin-2-ylmethanesulfonylmethyl,4-F-pyridin-3-ylmethanesulfonyl-methyl,3-F-pyridin-4-ylmethanesulfonylmethyl,isoquinolin-4-ylmethanesulfonylmethyl,6-phenylpyridin-2-ylmethanesulfonylmethyl,3-phenylpyridin-2-ylmethanesulfonylmethyl,4-phenylpyridin-3-ylmethanesulfonylmethyl,3-phenylpyridin-4-ylmethanesulfonylmethyl,2-(6-phenylpyridin-2-yl)ethanesulfonylmethyl,2-(3-phenylpyridin-2-yl)ethanesulfonylmethyl,2-(4-phenylpyridin-3-yl)methanesulfonylmethyl,2-(3-phenylpyridin-4-yl)ethanesulfonylmethyl,6-(pyridin-2-yl)pyridin-2-ylmethanesulfonylmethyl,3-(pyridin-2-yl)pyridin-2-ylmethane-sulfonylmethyl,4-(pyridin-2-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-2-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-2-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[3-(pyridin-2-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[4-(pyridin-2-yl)pyridin-3-yl]methanesulfonylmethyl,2-[3-(pyridin-2-yl)pyridin-4-yl]methanesulfonylmethyl,6-(pyridin-3-yl)pyridin-2-ylmethane-sulfonylmethyl,3-(pyridin-3-yl)pyridin-2-ylmethanesulfonylmethyl,4-(pyridin-3-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-3-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-3-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[3-(pyridin-3-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[4-(pyridin-3-yl)pyridin-3-yl]ethanesulfonylmethyl,2-[3-(pyridin-3-yl)pyridin-4-yl]methanesulfonylmethyl,6-(pyridin-4-yl)pyridin-2-ylmethanesulfonylmethyl,3-(pyridin-4-yl)pyridin-2-ylmethanesulfonylmethyl,4-(pyridin-4-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-4-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-4-yl)pyridin-2-yl]-ethanesulfonylmethyl,2-[3-(pyridin-4-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[4-(pyridin-4-yl)pyridin-3-yl]ethanesulfonylmethyl,2-[3-(pyridin-4-yl)pyridin-4-yl]ethanesulfonylmethyl,2,2-dimethylcyclopropylmethanesulfonylmethyl,biphen-2-ylmethanesulfonylmethyl,2-thiophen-2-ylphenylmethanesulfonylmethyl,2-thiazol-2-ylphenylmethanesulfonylmethyl,2-thiazol-5-ylphenylmethanesulfonylmethyl,2-[1.2.3]thiadiazol-5-ylphenylmethane-sulfonylmethyl,2-isoxazol-5-ylphenylmethanesulfonylmethyl,2-(1-methylpyrazol-5-yl)phenyl-methanesulfonylmethyl,2-[1.2.3]triazol-5-ylphenylmethanesulfonylmethyl,2-[1.2.3]oxadiazol-5-ylphenylmethanesulfonylmethyl,2-[(1.2.3)triazol-5-yl]phenylmethanesulfonylmethyl,2-[(1.2.3)triazol-1-yl]phenylmethanesulfonylmethyl,oxazolo[5,4-b]pyridin-2-ylmethane-sulfonylmethyl,oxazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,oxazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,benzimidazol-5-ylmethanesulfonylmethyl,benzimidazol-4-ylmethanesulfonylmethyl,3H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,3-CF₃.3H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃.3H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,1-CF₃-1H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,1-CF₃-1H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,thiazolo[5,4-b]pyridin-2-ylmethanesulfonylmethyl,thiazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,thiazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,5-CF₃thiazolo[5,4-b]pyridin-2-ylmethanesulfonylmethyl,4-CF₃-thiazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,7-CF₃-thiazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[2,3-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[3,2-c]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[3,2-b]pyridin-2-ylmethanesulfonylmethyl,imidazo[1,2-c]pyrimidin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-c]pyrimidin-2-methanesulfonylmethyl,imidazo[1,2-a]pyrimidin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-b]pyridazin-2-ylmethanesulfonylmethyl,imidazo[1,2-a]pyrazin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-a]pyrazin-2-methanesulfonylmethyl,pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,3-CF₃-pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,4-CF₃-pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,imidazo[1,2-d][1,2,4]triazin-2-methanesulfonylmethyl,3-CF₃-imidazo[1,2-d][1,2,4]triazin-2-methanesulfonylmethyl,[1,3]benzoxazol-2-ylmethanesulfonylmethyl,5-F-[1,3]benzoxazol-2-ylmethanesulfonylmethyl[1,3]benzoxazol-4-ylmethanesulfonylmethyl,2-CF₃-[1,3]benzoxazol-4-ylmethanesulfonyl-methyl,[1,3]benzoxazol-7-ylmethanesulfonylmethyl,2-CF₃-[1,3]benzoxazol-7-ylmethane-sulfonylmethyl,[1,2]benzoxazol-3-ylmethanesulfonylmethyl,[1,2]benzoxazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]benzoxazol-4-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzoxazol-4-ylmethanesulfonylmethyl,6-CF₃-[1,2]benzoxazol-7-ylmethane-sulfonylmethyl,6-CN-[1,2]benzoxazol-7-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzoxazol-7-ylmethanesulfonylmethyl,5-F-[1,2]benzoxazol-3-ylmethanesulfonylmethyl,[2,3]benzoxazol-7-ylmethanesulfonylmethyl,6-CF₃-[2,3]benzoxazol-7-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzoxazol-7-ylmethanesulfonylmethyl,5-CF₃-[2,3]benzoxazol-4-ylmethane-sulfonylmethyl,5-CN-[2,3]benzoxazol-4-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzoxazol-4-ylmethanesulfonylmethyl,benzothiazol-2-ylmethanesulfonylmethyl,5-F-benzothiazol-2-ylmethanesulfonylmethyl,benzothiazol-4-ylmethanesulfonylmethyl,2-CF₃-benzothiazol-4-ylmethanesulfonylmethyl,benzothiazol-7-ylmethanesulfonylmethyl,2-CF₃-benzothiazol-7-ylmethanesulfonylmethyl,[1,2]benzothiazol-3-ylmethanesulfonylmethyl,[1,2]benzothiazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]benzothiazol-4-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzothiazol-4-ylmethanesulfonylmethyl,6-CF₃-[1,2]benzothiazol-7-ylmethane-sulfonylmethyl,6-CN-[1,2]benzothiazol-7-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzothiazol-7-ylmethanesulfonylmethyl,5-F-[1,2]benzothiazol-3-ylmethanesulfonylmethyl,[2,3]benzothiazol-7-ylmethanesulfonylmethyl,6-CF₃-[2,3]benzothiazol-7-ylmethane-sulfonylmethyl,1-CF₃-[2,3]benzothiazol-7-ylmethanesulfonylmethyl,5-CF₃-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,5-CN-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,4-CF₃-2-CH₃-thiazol-5-ylmethanesulfonylmethyl,4-CF₃-thiazol-5-ylmethanesulfonylmethyl,4-CF₃-2-phenyl-thiazol-5-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-thiazol-4-ylmethanesulfonylmethyl,5-CF₃-thiazol-4-ylmethanesulfonylmethyl,5-CF₃-2-phenyl-thiazol-4-ylmethanesulfonylmethyl,5-CH₃-thiazol-2-ylmethanesulfonylmethyl,5-CF₃-thiazol-2-ylmethanesulfonylmethyl,5-phenyl-thiazol-2-ylmethanesulfonylmethyl,4-CH₃-thiazol-2-ylmethanesulfonylmethyl,4-CF₃-thiazol-2-ylmethanesulfonylmethyl,4-phenyl-thiazol-2-ylmethanesulfonylmethyl,5-CH₃-2-(pyridin-2-yl)-[1,2,3]triazol-4-ylmethanesulfonylmethyl,5-CF₃-2-(pyridin-2-yl)-[1,2,3]triazol-4-ylmethanesulfonylmethyl,5-CF₃-2-(4-methylsulfonylphenyl)-[1,2,3]thazol-4-ylmethane-sulfonylmethyl,4,5-dimethyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CF₃-4-CH₃-[1,2,4]triazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,5-CF₃-4-cyclopropyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,2,5-dimethyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,2-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,2-cyclopropyl-5-phenyl-[1,2,4]-triazol-3-ylmethanesulfonylmethyl,5-CF₃-1-CH₃-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,1-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CH₃-1-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,3-CH₃-[1,2,4]oxadiazol-5-ylmethanesulfonylmethyl,3-CF₃-[1,2,4]oxadiazol-5-ylmethanesulfonylmethyl,3-phenyl-[1,2,4]oxadiazol-5-ylmethane-sulfonylmethyl,5-CH₃-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,5-CF₃-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,5-phenyl-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,2-CH₃-[1,3,4]oxadiazol-5-ylmethanesulfonylmethyl,2-CF₃-[1,3,4]oxadiazol-5-ylmethane-sulfonylmethyl,2-phenyl-[1,3,4]oxadiazol-5-ylmethanesulfonylmethyl,3-CH₃-[1,2,4]thiadiazol-5-ylmethanesulfonylmethyl,3-CF₃-[1,2,4]thiadiazol-5-ylmethanesulfonylmethyl,3-phenyl-[1,2,4]thiadiazol-5-ylmethanesulfonylmethyl,5-CH₃-[1,2,4]thiadiazol-3-ylmethane-sulfonylmethyl,5-CF₃-[1,2,4]thiadiazol-3-ylmethanesulfonylmethyl,5-phenyl-[1,2,4]thiadiazol-3-ylmethanesulfonylmethyl,2-CH₃-[1,3,4]thiadiazol-5-ylmethanesulfonylmethyl,2-CF₃-[1,3,4]thiadiazol-5-ylmethanesulfonylmethyl,2-phenyl-[1,3,4]thiadiazol-5-ylmethane-sulfonylmethyl,2,2-difluoropyrrolidinylmethanesulfonylmethyl,3,3-difluoropyrroalinyl-methanesulfonylmethyl,3-CF₃—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,3-CN—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-CF₃—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-(1-CH₃-1-hydroxyethyl)-N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,1,3-dimethylpynol-2-ylmethane-sulfonylmethyl,4-CF₃—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,4-CN—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,4-CN—N-(3,3,3-trifluoropropyl)-pyrrol-3-ylmethanesulfonylmethyl,2-CF₃—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,2-CF₃—N-phenyl-pyrrol-3-ylmethane-sulfonylmethyl,4-CF₃-pyrrol-2-ylmethanesulfonylmethyl,4-(1-CH₃-1-hydroxyethyl)-pyrrol-2-ylmethanesulfonylmethyl,3-CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-CF₃-pyrrol-3-ylmethane-sulfonylmethyl,2-CF₃-pyrrol-3-ylmethanesulfonylmethyl,3-CF₃-pyrrol-2-ylmethane-sulfonylmethyl,2-CF₃-pyrrol-4-ylmethanesulfonylmethyl,2-CF₃—N—CH₃-pyrrol-4-ylmethane-sulfonylmethyl,3-CF₃-fur-2-ylmethanesulfonylmethyl, 3-CN-fur-2-ylmethanesulfonylmethyl,3-CF₃-fur-4-ylmethanesulfonylmethyl, 3-CN-fur-4-ylmethanesulfonylmethyl,2-CF₃-fur-3-ylmethanesulfonylmethyl,3-CF₃-thiazol-2-ylmethanesulfonylmethyl,3-CN-thiazol-2-ylmethanesulfonylmethyl,3-CF₃-thiazol-4-ylmethanesulfonylmethyl,3-CN-thiazol-4-ylmethanesulfonylmethyl,2-CF₃-thiazol-3-ylmethanesulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-5-ylmethanesulfonylmethyl,N—CH₃-3-(1-CH₃-1-hydroxyethyl)-1H-pyrazol-5-ylmethane-sulfonylmethyl,N—CH₃-3-phenyl-1H-pyrazol-5-ylmethanesulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,N—CH₃-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl,N-phenyl-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl,N-phenyl-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,N-phenyl-5-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,(N—CH₃-4-CF₃-1H-imidazol-2-ylmethane)-sulfonylmethyl,[N—CH₃-4-(1-CH₃-1-hydroxyethyl)-1H-imidazol-2-ylmethane]-sulfonylmethyl,(N—CH₃-4-phenyl-1H-imidazol-2-ylmethane)-sulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,(N—CH₃-2-CF₃-1H-imidazol-5-ylmethane)-sulfonylmethyl,(N—CH₃-2-phenyl-1H-imidazol-5-ylmethane)-sulfonylmethyl,(N—CH₃-5-CF₃-1H-imidazol-4-ylmethane)-sulfonylmethyl,(N-phenyl-5-CF₃-1H-imidazol-4-ylmethane)-sulfonylmethyl,4-CN-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CN-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CN-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CN-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CN-isothiazol-5-ylmethanesulfonylmethyl,4-CN-3-phenyl-isothiazol-5-ylmethanesulfonylmethyl,4-CN-isothiazol-3-ylmethanesulfonylmethyl,4-CN-5-phenyl-isothiazol-3-ylmethane-sulfonylmethyl,4-CF₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl.3-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,3-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CH₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,3-CH₃-[1,2]oxazol-4-ylmethane-sulfonylmethyl,5-CH₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CH₃-isothiazol-5-ylmethane-sulfonylmethyl,4-CH₃-3-phenyl-isothiazol-5-ylmethanesulfonylmethyl,4-CH₃-isothiazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-isothiazol-3-ylmethanesulfonylmethyl,3-CH₃-isothiazol-4-ylmethanesulfonylmethyl,5-CH₃-isothiazol-4-ylmethanesulfonylmethyl,4-CF₃-2-CH₃-[1,3]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,3]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-2-phenyl-[1,3]oxazol-5-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-[1,3]oxazol-4-yl-methanesulfonylmethyl,5-CF₃-[1,3]oxazol-4-ylmethanesulfonylmethyl,5-CF₃-2-phenyl-[1,3]oxazol-4-ylmethanesulfonylmethyl,5-CH₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,5-CF₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,5-phenyl-[1,3]oxazol-2-ylmethane-sulfonylmethyl,4-CH₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,4-CF₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,4-phenyl-[1,3]oxazol-2-ylmethanesulfonylmethyl,N-methyl-indol-2-ylmethanesulfonylmethyl,3-CF₃-indol-2-ylmethanesulfonylmethyl,3-CF₃—N-methyl-indol-2-ylmethanesulfonylmethyl,5-fluoro-N-methyl-indol-2-ylmethanesulfonylmethyl,N-methyl-indol-3-ylmethanesulfonylmethyl,2-CF₃-indol-3-ylmethanesulfonylmethyl,2-CF₃—N-methyl-indol-3-ylmethanesulfonylmethyl,5-fluoro-N-methyl-indol-3-ylmethanesulfonylmethyl,5-CF₃—N-methyl-indol-4-ylmethanesulfonylmethyl,5-CN—N-methyl-indol-4-ylmethane-sulfonylmethyl,2-CF₃—N-methyl-indol-4-ylmethanesulfonylmethyl,3-CF₃—N-methyl-indol-4-ylmethanesulfonylmethyl,6-CF₃—N-methyl-indol-7-ylmethanesulfonylmethyl,6-CN—N-methyl-indol-7-ylmethanesulfonylmethyl,2-CF₃—N-methyl-indol-7-ylmethanesulfonylmethyl,3-CF₃—N-methyl-indol-7-ylmethanesulfonylmethyl,benzofuran-2-ylmethanesulfonylmethyl,3-CF₃-benzofuran-2-ylmethanesulfonylmethyl,3-CN-benzofuran-2-ylmethanesulfonylmethyl,5-F-benzofuran-2-ylmethanesulfonylmethyl,benzofuran-3-ylmethanesulfonylmethyl,2-CF₃-benzofuran-3-ylmethanesulfonylmethyl,2-CH₃-benzofuran-3-ylmethanesulfonylmethyl,5-F-benzofuran-3-ylmethanesulfonylmethyl,5-CF₃-benzofuran-4-ylmethanesulfonylmethyl,5-CN-benzofuran-4-ylmethanesulfonylmethyl,2-CF₃-benzofuran-4-ylmethanesulfonylmethyl,3-CF₃-benzofuran-4-ylmethanesulfonylmethyl,6-CF₃-benzofuran-7-ylmethanesulfonylmethyl,6-CN-benzofuran-7-ylmethanesulfonylmethyl,2-CF₃-benzofuran-7-ylmethanesulfonylmethyl,3-CF₃-benzofuran-7-ylmethanesulfonylmethyl,benzothien-2-ylmethanesulfonylmethyl,(3-CF₃-benzothien-2-ylmethane)-sulfonylmethyl,(3-CN-benzothien-2-ylmethane)-sulfonylmethyl,(5-F-benzothien-2-ylmethane)-sulfonylmethyl,benzothien-3-ylmethanesulfonylmethyl,(2-CF₃-benzothien-3-ylmethane)-sulfonylmethyl,(2-CH₃-benzothien-3-ylmethane)-sulfonylmethyl,(5-fluoro-benzothien-3-ylmethane)-sulfonylmethyl,(5-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(5-CN-benzothien-4-ylmethane)-sulfonylmethyl,(2-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(3-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(6-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,(6-CN-benzothien-7-ylmethane)-sulfonylmethyl,(2-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,(3-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,N-methyl-benzimidazol-2-ylmethanesulfonylmethyl,(5-fluoro-N-methyl-benzimidazol-2-ylmethane)-sulfonylmethyl,(N-methyl-indazol-3-ylmethane)-sulfonylmethyl,(5-fluoro-N-methyl-indazol-3-ylmethane)-sulfonylmethyl,(2-CF₃—N-methyl-benzimidazol-4-ylmethane)-sulfonylmethyl,(2-CF₃—N-methyl-benzimidazol-7-ylmethane)-sulfonylmethyl,(N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(5-CF₃—N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(3-CF₃—N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(6-CF₃—N-methyl-indazol-7-ylmethane)-sulfonylmethyl,(6-CN—N-methyl-indazol-7-ylmethane)-sulfonylmethyl, or(3-CF₃—N-methyl-indazol-7-ylmethane)-sulfonylmethyl.
 8. The compound ofclaim 7 wherein R¹ and R² together with the carbon atom to which theyare attached form cycloalkylene.
 9. The compound of claim 7 wherein R¹and R² together with the carbon atom to which they are attached formpiperidin-4-yl substituted at the nitrogen with ethyl, trifluoroethyl orcyclopropyl.
 10. The compound of claim 7 wherein R¹ and R² together withthe carbon atom to which they are attached form tetrahydropyran-4-yl,tetrahydrothiopyran-4-yl, or 1,1-dioxohexahydrothiopyran-4-yl.
 11. Acompound selected from the group consisting of:N-(1-cyanocyclopropyl)-3-(4-trifluoromethylpyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(5)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-pyridin-3-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide,N-(1-cyanocyclopropyl)-3-pyridan-3-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-trifluoromethylfuran-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-pyrimidin-5-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-methylthiazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-pyridin-4-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-pyrimidin-4-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-[2-(1-oxopyn-ol-1-ylmethanesulfonyl]-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-pyridin-3-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-3-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(3,3,3-trifluoropropane-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-trifluoromethylpyridin-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(4-[1.2.4]-triazol-1-ylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-[2-(2-oxo-2,3-dihydrobenzimidazol-1-ylmethanesulfonyl]-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(5-oxo-pyrrolidin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylaminopropionamide;N-(1-cyanocyclopropyl)-3-(2-fluoropyridin-3-ylmethanesulfonyll)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylaminopropionamide;N-(1-cyanocyclopropyl)-3-(3-methyloxetan-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-phenylethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(3,3,3-trifluoropropane-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(fluoropyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(fluoropyrazin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(difluoropyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(difluoropyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(quinolin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(benzo[1.2.5]thiadiazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(benzothiazol-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(5-methylisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-methylpropylsulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclobutylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2,6-difluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2,4-difluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(quinolin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(4,4,4-trifluorobutyl-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-trifluoromethylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(2-trifluoromethoxyphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,5-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,5-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-pyridin-2-ylethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-pyridin-3-ylethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(quinolin-8-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,3-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,4-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(5-methyl-3-phenylisoxazol-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(4-methyl-2-phenyl-[1.2.3]triazol-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(2-cyanophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(3-methoxycarbonylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2-difluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(RS)-2-chloropyridin-5-ylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide,N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide;N-(1-cyanocyclopropyl)-3-(1-oxopyridin-3-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide;N-(1-cyanocyclopropyl)-3-(quinoxalin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(tetrahydropyran-2RS-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(2,6-dichlorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(3-methoxycarbonylfuran-2RS-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(5-methylisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)-propionamide;N-(1-cyanocyclopropyl)-3-(2,2-dimethylpropylsulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(R)-4-fluorophenylpropylamino)propionamide;N-(1-cyanocyclopropyl)-3-(ethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,5-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,6-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,6-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,3-difluorophenylethylamino)propionamide,N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,4-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(methanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(propane-1-sulfonyl)-2(R)-(2,2,2-trifluoro-1(5)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(1H-indol-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,4-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(pyridin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3,4-difluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-[2-(1H-indol-3-ylmethanesulfonyl]-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(tetrahydropyran-4-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2,3,4-trifluorophenylethylamino)propionamide,N-(1-cyanocyclopropyl)-3-(cyclopropylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(R)-2,3,4-trifluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2,2,2-trifluoroethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(benzisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-2-fluorophenylethylamino)propionamide;N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(RS)-(3-hydroxy-6-methyl-pyridin-2-yl)-ethylamino]-propionamide;N-(1-cyanocyclopropyl)-3-(2-tert-butyl-[1.3.4]-thiadiazol-5-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2,4,6-trifluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;N-(1-cyanocyclopropyl)-3-(2-pyridin-2-ylethanesulfonyl)-2(R)-(2,2,3,3,3-pentafluoro-1(S)-4-fluorophenylpropylamino)propionamide;N-(1-cyanocyclopropyl)-3-(1-ethyl-2,5-dioxopyrrolidin-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;andN-(1-cyanocyclopropyl)-3-(benzisoxazol-3-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamideor a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising a compound of claim 1 in admixture with one ormore suitable excipients.
 13. A method for treating a disease in ananimal mediated by Cathepsin S which method comprises administering tothe animal a pharmaceutical composition comprising a compound of claim11 in admixture with one or more suitable excipients.
 14. The method ofclaim 12 wherein the disease is rheumatoid arthritis, multiplesclerosis, myasthenia gravis, psoriasis, pemphigus vulgaris, Graves'disease, myasthenia gravis, systemic lupus erythemotasus, asthma, pain,and atherosclerosis.
 15. A method of treating a patient undergoing atherapy wherein the therapy causes an immune response in the patientcomprising administering to the patient a compound of claim 1.